Anti-inflammatory phosphonate compounds

ABSTRACT

The invention is related to phosphorus substituted anti-inflammatory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

PRIORITY OF INVENTION

This application claims the benefit of priority under 35 U.S.C. § 119(e)to U.S. Provisional Patent Application Ser. Nos. 60/465,181, 60/465,683,60/465,682, 60/465,620, 60/465,452, 60/465,449, 60/465,335, 60/465,547,60/465,695, 60/465,746, 60/465,406, 60/465,479, 60/465,480, 60/465,749,60/465,638, 60/465,332, 60/465,560, 60/465,422, 60/465,342, 60/465,632,60/465,640, 60/465,756, 60/465,424, 60/465,373, 60/465,420, 60/465,380,60/465,433, 60/465,419, 60/465,481, 60/465,377, 60/465,844, 60/465,658,60/465,581, 60/465,532, and 60/465,531, all filed Apr. 25, 2003; to U.S.Provisional Patent Application Ser. Nos. 60/493,310, 60/493,309,60/493,303, and 60/493,302, all filed Aug. 7, 2003; to U.S. ProvisionalPatent Application Ser. Nos. 60/495,427, 60/495,389, 60/495,366,60/495,563, 60/495,295, 60/495,532, 60/495,414, 60/495,757, 60/495,380,60/495,680, 60/495,679, 60/495,749, 60/495,748, 60/495,597, 60/495,471,60/495,691, 60/495,276, 60/495,754, 60/495,472, 60/495,530, 60/495,375,60/495,274, 60/495,533, 60/495,529, 60/495,455, 60/495,537, 60/495,456,60/495,660, 60/495,398, 60/495,425, 60/495,393, 60/495,460, 60/495,416,60/495,427, 60/495,561, and 60/495,614, all filed Aug. 15, 2003; to U.S.Provisional Patent Application Ser. Nos. 60/514,072, 60/514,054,60/513,971, 60/514,394, 60/514,393, 60/513,950, 60/513,945, 60/513,944,60/513,947, 60/513,975, 60/514,453, 60/514,464, 60/514,203, 60/513,953,60/514,450, 60/514,244, 60/514,466, 60/513,973, 60/514,202, 60/514,424,60/513,970, 60/514,324, 60/514,111, 60/514,110, 60/514,334, 60/514,085,60/514,130, 60/513,961, 60/514,131, 60/514,200, 60/514,280, 60/514,098,60/513,977, 60/514,174, 60/513,924, 60/514,143, 60/514,144, 60/513,951,60/514,206, 60/514,160, 60/514,326, 60/514,205, 60/513,979, 60/514,075,60/513,946, 60/514,051, 60/514,161, 60/514,204, 60/514,325, 60/514,044,60/514,201, 60/514,522, 60/514,175, 60/514,113, 60/514,097, 60/514,360,60/513,976, 60/514,107, 60/513,982, 60/514,116, 60/513,562, 60/513,592,60/513,563, 60/513,530, 60/513,579, 60/514,298, 60/513,531, 60/513,561,60/513,589, 60/513,588, 60/514,258, 60/513,948, 60/514,140, 60/513,593,and 60/514,021 all filed Oct. 24, 2003; to U.S. Provisional PatentApplication Ser. No. 60/532,591, filed Dec. 1, 2003; to U.S. ProvisionalPatent Application Ser. Nos. 60/532,257, 60/532,230, 60/531,960,60/532,160, and 60/531,940, all filed Dec. 22, 2003; to U.S. ProvisionalApplication Ser. No. 60/532,591, filed Dec. 23, 2003, and to U.S.Provisional Patent Application Ser. Nos. 60/536,003, 60/536,027,60/536,180, 60/536,005, 60/536,004, and to 60/536,009, all filed Jan.12, 2004. The entirety of each Provisional Application listed above isincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates generally to phosphonate containing compounds withanti-inflammatory activity.

BACKGROUND OF THE INVENTION

Improving the delivery of drugs and other agents to target cells andtissues has been the focus of considerable research for many years.Though many attempts have been made to develop effective methods forimporting biologically active molecules into cells, both in vivo and invitro, none has proved to be entirely satisfactory. Optimizing theassociation of the inhibitory drug with its intracellular target, whileminimizing intercellular redistribution of the drug, e.g., toneighboring cells, is often difficult or inefficient.

Most agents currently administered to a patient parenterally are nottargeted, resulting in systemic delivery of the agent to cells andtissues of the body where it is unnecessary, and often undesirable. Thismay result in adverse drug side effects, and often limits the dose of adrug (e.g., glucocorticoids and other anti-inflammatory drugs) that canbe administered. By comparison, although oral administration of drugs isgenerally recognized as a convenient and economical method ofadministration, oral administration can result in either (a) uptake ofthe drug through the cellular and tissue barriers, e.g., blood/brain,epithelial, and cell membrane, resulting in undesirable systemicdistribution, or (b) temporary residence of the drug within thegastrointestinal tract. Accordingly, a major goal has been to developmethods for specifically targeting agents to cells and tissues. Benefitsof such treatment includes avoiding the general physiological effects ofinappropriate delivery of such agents to other cells and tissues, suchas uninfected cells.

Inflammation is a major problem for many people. Thus, there is a needfor novel anti-inflammatory agents, e.g. drugs, having improvedanti-inflammation properties, pharmacokinetic properties, activity, oralbioavailability, potency, or effective half-lives in vivo. Such agentsmay also have distinct resistance profiles, fewer side effects, lesscomplicated dosing schedules, or have increased oral activity.

There is also a need for assay methods capable of determining thepresence, absence or amounts of inflammation. Such methods would be ofpractical utility in the search for inhibitors as well as for diagnosingthe presence of inflammation.

SUMMARY OF THE INVENTION

Intracellular targeting may be achieved by methods and compositions thatallow accumulation or retention of biologically active agents insidecells. The present invention provides novel phosphonate containinganalogs of anti-inflammatory compounds. These compounds possess theutilities of the related anti-inflammatory compounds, but due to thepresence of the phosphonate group(S) they typically provide cellularaccumulation of the analog. Thus, compounds of the invention maydemonstrate improved anti-inflammatory properties, pharmacokineticproperties, oral bioavailability, potency, or extended effectivehalf-life in vivo, or a combination thereof. The compounds of theinvention may also have distinct resistance profiles, fewer sideeffects, less complicated dosing schedules, or have increased oralactivity.

The present invention relates generally to the accumulation or retentionof therapeutic compounds inside cells. The invention is moreparticularly related to attaining high concentrations ofphosphonate-containing molecules in target cells. Such effectivetargeting may be applicable to a variety of therapeutic formulations andprocedures.

Accordingly, in one embodiment the invention provides a compound of theinvention which is a conjugate comprising an anti-inflammatory compoundlinked to one or more phosphonate groups; or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment the invention provides a compound of theinvention, or a pharmaceutically acceptable salt or solvate thereof,that is a compound of any one of formulae 500-611:

that is substituted with one or more groups A⁰, wherein:

-   A⁰ is A¹, A² or W,³ with the proviso that the conjugate includes at    least one A¹;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));    -   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or        —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorous atoms        Y² can also be C(R²)(R²);    -   R^(x) is independently H, R¹, R², W³, a protecting group, or the        formula:    -   wherein:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R¹ is independently H or alkyl of 1 to 18 carbon atoms;    -   R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is        independently substituted with 0 to 3 R³ groups or taken        together at a carbon atom, two R² groups form a ring of 3 to 8        carbons and the ring may be substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),        —N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;    -   M2 is 0, 1 or 2;    -   M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M1a, M1c, and M1d are independently 0 or 1;    -   M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   X⁶⁶ is hydrogen or fluorine; and    -   X⁶⁷ is hydrogen, hydroxy, or acyloxy.

In another embodiment the invention provides a compound of the inventionwhich is a compound of the formula:[DRUG]-(A⁰)_(nn)or a pharmaceutically acceptable salt thereof wherein,

-   -   DRUG is a compound of any one of formulae 500-611:    -   nn is 1, 2, or 3;    -   A⁰ is A¹, A² or W³ with the proviso that the compound includes        at least one A¹;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));    -   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or        —S(O)_(M2)—S(O)_(M2)—;    -   R^(x) is independently H, R¹, W³, a protecting group, or the        formula:    -   wherein:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R¹ is independently H or alkyl of 1 to 18 carbon atoms;    -   R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is        independently substituted with 0 to 3 R³ groups or taken        together at a carbon atom, two R² groups form a ring of 3 to 8        carbons and the ring may be substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),        —N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   R^(5a), is independently alkylene of 1 to 18 carbon atoms,        alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon        atoms any one of which alkylene, alkenylene or alkynylene is        substituted with 0-3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;    -   M2 is 0, 1 or 2;    -   M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M1a, M1c, and M1d are independently 0 or 1;    -   M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   X⁶⁶ is hydrogen or fluorine; and    -   X⁶⁷ is hydrogen, hydroxy, or acyloxy.

In another embodiment the invention provides a compound of the inventionwhich is a compound of any one of formulae 1-296:

wherein:

-   -   A⁰ is A¹, A² or W³ with the proviso that one A⁰ is A¹;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));    -   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or        —S(O)_(M2)—S(O)_(M2)—;    -   R^(x) is independently H, R¹, W³, a protecting group, or the        formula:    -   wherein:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R¹ is independently H or alkyl of 1 to 18 carbon atoms;    -   R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is        independently substituted with 0 to 3 R³ groups or taken        together at a carbon atom, two R² groups form a ring of 3 to 8        carbons and the ring may be substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),        —N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   R^(5a) is independently alkylene of 1 to 18 carbon atoms,        alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon        atoms any one of which alkylene, alkenylene or alkynylene is        substituted with 0-3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;    -   M2 is 0, 1 or 2;    -   M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M1a, M1c, and M1d are independently 0 or 1;    -   M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   X⁵⁰ is H or F;    -   X⁵¹ is H, hydroxy, or acyloxy;    -   X⁵² is NH₂ or EtC(O)N—Na+;    -   X⁵³ is H, methyl, CF₃, or halo;    -   X⁵⁴ is H, halo, trifluoromethyl, (C1-C3)alkyl, cyano, or        (C₁-C₃)alkoxy;    -   X⁵⁵ is H, F, Cl, Br, methyl, or trifluoromethyl;    -   X⁵⁶ is hydrogen, halo, trifluoromethyl, cyano, methyl;    -   X⁵⁷ is H, F, Cl, CF₃, cyano, methyl, or t-butyl;    -   X⁵⁸ is H or CH₂OH;    -   X⁵⁹ is H or F;    -   X⁶⁰ is H, trifluoromethyl, or cyano;    -   X⁶¹ is methoxy, ethoxy, propoxy, difluoromethoxy,        trifluoromethoxy, vinyl, ethyl, methyl, propyl, butyl,        cyclopropyl, N-methylamino, or N-formylamino;    -   X⁶² is methyl, chloro, or trifluoromethyl;    -   X⁶³ is H, methyl, ethyl, cyclopropyl, vinyl, or trifluoromethyl;    -   X⁶⁴ is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl,        3-methyl-1-buten-1-yl;    -   X⁶⁵ is H or F; and    -   Ar is aryl or heteroaryl.

The invention also provides a pharmaceutical composition comprising aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable diluent or carrier.

This invention also pertains to a method of increasing cellularaccumulation and retention of an anti-inflammatory drug compoundcomprising linking the compound to one or more phosphonate groups.

The invention also provides a method of treating inflammation in amammal, comprising administering a compound of the invention to themammal.

The invention also provides a compound of the invention for use inmedical therapy (preferably for use in treating inflammation, as well asthe use of a compound of the invention for the manufacture of amedicament useful for the treatment of inflammation.

In another aspect the invention also provides a method for inhibitinginflammatory activity comprising contacting a sample in need of suchtreatment with a compound or composition of the invention.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of the invention are useful to prepare other compoundsof the invention.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated claims, it will be understood that they are not intended tolimit the invention to those claims. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims.

Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When tradenames are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(S) of the tradename product.

“Bioavailability” is the degree to which the pharmaceutically activeagent becomes available to the target tissue after the agent'sintroduction into the body. Enhancement of the bioavailability of apharmaceutically active agent can provide a more efficient and effectivetreatment for patients because, for a given dose, more of thepharmaceutically active agent will be available at the targeted tissuesites.

The terms “phosphonate” and “phosphonate group” include functionalgroups or moieties within a molecule that comprises a phosphorous thatis 1) single-bonded to a carbon, 2) double-bonded to a heteroatom, 3)single-bonded to a heteroatom, and 4) single-bonded to anotherheteroatom, wherein each heteroatom can be the same or different. Theterms “phosphonate” and “phosphonate group” also include functionalgroups or moieties that comprise a phosphorous in the same oxidationstate as the phosphorous described above, as well as functional groupsor moieties that comprise a prodrug moiety that can separate from acompound so that the compound retains a phosphorous having thecharacteriatics described above. For example, the terms “phosphonate”and “phosphonate group” include phosphonic acid, phosphonic monoester,phosphonic diester, phosphonamidate, and phosphonthioate functionalgroups. In one specific embodiment of the invention, the terms“phosphonate” and “phosphonate group” include functional groups ormoieties within a molecule that comprises a phosphorous that is 1)single-bonded to a carbon, 2) double-bonded to an oxygen, 3)single-bonded to an oxygen, and 4) single-bonded to another oxygen, aswell as functional groups or moieties that comprise a prodrug moietythat can separate from a compound so that the compound retains aphosphorous having such characteriatics. In another specific embodimentof the invention, the terms “phosphonate” and “phosphonate group”include functional groups or moieties within a molecule that comprises aphosphorous that is 1) single-bonded to a carbon, 2) double-bonded to anoxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bondedto another oxygen or nitrogen, as well as functional groups or moietiesthat comprise a prodrug moiety that can separate from a compound so thatthe compound retains a phosphorous having such characteriatics.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.active ingredient, as a result of spontaneous chemical reaction(S),enzyme catalyzed chemical reaction(S), photolysis, and/or metabolicchemical reaction(S). A prodrug is thus a covalently modified analog orlatent form of a therapeutically-active compound.

“Prodrug moiety” refers to a labile functional group which separatesfrom the active inhibitory compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with thephosphonate prodrug compounds of the invention include, but are notlimited to, amidases, esterases, microbial enzymes, phospholipases,cholinesterases, and phosphases. Prodrug moieties can serve to enhancesolubility, absorption and lipophilicity to optimize drug delivery,bioavailability and efficacy. A prodrug moiety may include an activemetabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂C(═O)R⁹ and acyloxymethyl carbonates—CH₂C(═O)OR⁹ where R⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂C(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC)—CH₂C(═O)OC(CH₃)₃.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to thephosphate have also been described (Khamnei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate the parentphosphonic acid. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatethe phosphoric acid and the quinone methide intermediate. Examples ofthis class of prodrugs are described by Mitchell et al. (1992) J. Chem.Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have alsobeen described as prodrugs of phosphorus-containing compounds (Erion etal., U.S. Pat. No. 6,312,662).

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Any reference to any of the compounds of the invention also includes areference to a physiologically acceptable salt thereof. Examples ofphysiologically acceptable salts of the compounds of the inventioninclude salts derived from an appropriate base, such as an alkali metal(for example, sodium), an alkaline earth (for example, magnesium),ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl). Physiologicallyacceptable salts of a compound having an amino group include salts oforganic carboxylic acids such as acetic, benzoic, lactic, fumaric,tartaric, maleic, malonic, malic, isethionic, lactobionic and succinicacids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, suchas hydrochloric, sulfuric, phosphoric and sulfamic acids.Physiologically acceptable salts of a compound having a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will typically be physiologically acceptable, i.e. they willbe salts derived from a physiologically acceptable acid or base.However, salts of acids or bases which are not physiologicallyacceptable may also find use, for example, in the preparation orpurification of a physiologically acceptable compound. All salts,whether or not derived form a physiologically acceptable acid or base,are within the scope of the present invention.

“Alkyl” is C₁-C₁₈ hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms. Examples are methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. Examples include, but are not limitedto, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), 5-hexenyl (—CH₂ CH₂CH₂CH₂CH═CH₂), and 2,5-hexadienyl(—CH₂CH═CHCH₂CH═CH₂).

“Alkynyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. Examples include, but are not limited to,acetylenic (—C≡CH), propargyl (—CH₂C≡CH), and 2,5-hexadiynyl (—CH₂C≡CHCH₂C≡CH)

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical of 1-18 carbon atoms, and having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent alkane. Typical alkyleneradicals include, but are not limited to, methylene (—CH₂—) 1,2-ethyl(—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene. Typicalalkenylene radicals include, but are not limited to, 1,2-ethylene(—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkyne. Typicalalkynylene radicals include, but are not limited to, acetylene (—C≡C—),propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C—CH—).

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Typical aryl groups include, butare not limited to, radicals derived from benzene, substituted benzene,naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenylor alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl”, and “substituted arylalkyl”mean alkyl, aryl, and arylalkyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R, —O⁻, —OR, —SR, —S⁻, —NR₂, —NR₃, ═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O,—NCS, —NO, —NO₂, ═N₂, —N₃, NC(═O)R, —C(═O)R, —C(═O)NRR—S(═O)₂O⁻,—S(═O)₂OH, —S(═O)₂R, —OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)O₂RR,—P(═O)O₂RR, —P(═O)(O⁻)₂, —P(═O)(OH)₂, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR,—C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, —C(NR)NRR, whereeach X is independently a halogen: F, Cl, Br, or I; and each R isindependently —H, alkyl, aryl, heterocycle, protecting group or prodrugmoiety. Alkylene, alkenylene, and alkynylene groups may also besimilarly substituted.

“Heterocycle” as used herein includes by way of example and notlimitation these heterocycles described in Paquette, Leo A.; Principlesof Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry ofHeterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of theinvention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S).

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles can bebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles canbe bonded at position 1 of an aziridine, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,position 2 of a isoindole, or isoindoline, position 4 of a morpholine,and position 9 of a carbazole, or β-carboline. Still more typically,nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring having3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle,and up to about 20 carbon atoms as a polycycle. Monocyclic carbocyclestypically have 3 to 6 ring atoms, still more typically 5 or 6 ringatoms. Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples ofmonocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryland naphthyl.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(S). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or 1 meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. The PG groups do not need to be, and generally are not, thesame if the compound is substituted with multiple PG. In general, PGwill be used to protect functional groups such as carboxyl, hydroxyl,thio, or amino groups and to thus prevent side reactions or to otherwisefacilitate the synthetic efficiency. The order of deprotection to yieldfree, deprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether- nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,New York, 1994), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3,Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages155-184. For protecting groups for carboxylic acid, phosphonic acid,phosphonate, sulfonic acid and other protecting groups for acids seeGreene as set forth below. Such groups include by way of example and notlimitation, esters, amides, hydrazides, and the like.

Ether- and Ester-Forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, suchas phosphonamidate esters, phosphorothioate esters, phosphonate esters,and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3)sulphur ester-forming groups, such as sulphonate, sulfate, andsulfinate.

The phosphonate moieties of the compounds of the invention may or maynot be prodrug moieties, i.e. they may or may be susceptible tohydrolytic or enzymatic cleavage or modification. Certain phosphonatemoieties are stable under most or nearly all metabolic conditions. Forexample, a dialkylphosphonate, where the alkyl groups are two or morecarbons, may have appreciable stability in vivo due to a slow rate ofhydrolysis.

Within the context of phosphonate prodrug moieties, a large number ofstructurally-diverse prodrugs have been described for phosphonic acids(Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)and are included within the scope of the present invention. An exemplaryphosphonate ester-forming group is the phenyl carbocycle in substructureA₃ having the formula:

-   -   wherein R₁ may be H or C₁-C₁₂ alkyl; m1 is 1, 2, 3, 4, 5, 6, 7        or 8, and the phenyl carbocycle is substituted with 0 to 3 R₂        groups. Where Y₁ is O, a lactate ester is formed, and where Y₁        is N(R₂), N(OR₂) or N(N(R₂)₂, a phosphonamidate ester results.

In its ester-forming role, a protecting group typically is bound to anyacidic group such as, by way of example and not limitation, a —CO₂H or—C(S)OH group, thereby resulting in —CO₂R^(x) where R^(x) is definedherein. Also, R^(x) for example includes the enumerated ester groups ofWO 95/07920.

Examples of protecting groups include:

-   -   C₃-C₁₂ heterocycle (described above) or aryl. These aromatic        groups optionally are polycyclic or monocyclic. Examples include        phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and        4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4-        and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl,        1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,    -   C₃-C₁₂ heterocycle or aryl substituted with halo, R¹,        R¹—O—C₁-C₁₂ alkylene, C₁-C₁₂ alkoxy, CN, NO₂, OH, carboxy,        carboxyester, thiol, thioester, C₁-C₁₂ haloalkyl (1-6 halogen        atoms), C₂-C₁₂ alkenyl or C₂-C₁₂ alkynyl. Such groups include        2-, 3- and 4-alkoxyphenyl (C₁-C₁₂ alkyl), 2-, 3- and        4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-,        2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and        3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl,        2- and 3-ethoxy-5-hydroxyphenyl, 2- and        3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3-        and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl,        2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and        2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and        3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and        3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and        3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and        3,5-dihalophenyl (including 2,4-difluorophenyl and        3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5        halogen atoms, C₁-C₁₂ alkyl including 4-trifluoromethylphenyl),        2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and        4-haloalkylbenzyl (1 to 5 halogen atoms, C₁-C₁₂ alkyl including        4-trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl        and 2-, 3- and 4-trichloromethylphenyl), 4-N-methylpiperidinyl,        3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl,        alkylsalicylphenyl (C₁-C₄ alkyl, including 2-, 3- and        4-ethylsalicylphenyl), 2-,3- and 4-acetylphenyl,        1,8-dihydroxynaphthyl (—C₁₀H₆—OH) and aryloxy ethyl [C₆-C₉ aryl        (including phenoxy ethyl)], 2,2′-dihydroxybiphenyl, 2-, 3- and        4-N,N-dialkylaminophenol, —C₆H₄CH₂—N(CH₃)₂, trimethoxybenzyl,        triethoxybenzyl, 2-alkyl pyridinyl (C₁₋₄ alkyl);        esters of 2-carboxyphenyl; and C₁-C₄ alkylene-C₃-C₆ aryl        (including benzyl, —CH₂-pyrrolyl, —CH₂-thienyl, —CH₂-imidazolyl,        —CH₂-oxazolyl, —CH₂-isoxazolyl, —CH₂-thiazolyl,        —CH₂-isothiazolyl, —CH₂-pyrazolyl, —CH₂-pyridinyl and        —CH₂-pyrimidinyl) substituted in the aryl moiety by 3 to 5        halogen atoms or 1 to 2 atoms or groups selected from halogen,        C₁-C₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH,        C₁-C₁₂ haloalkyl (1 to 6 halogen atoms; including —CH₂CCl₃),        C₁-C₁₂ alkyl (including methyl and ethyl), C₂-C₁₂ alkenyl or        C₂-C₁₂ alkynyl; alkoxy ethyl [C₁-C₆ alkyl including        —CH₂—CH₂—O—CH₃ (methoxy ethyl)]; alkyl substituted by any of the        groups set forth above for aryl, in particular OH or by 1 to 3        halo atoms (including —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₃,        —(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃, —CH₂CH₂F,        —CH₂CH₂Cl, —CH₂CF₃, and —CH₂CCl₃);        —N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol,        catechol monoester, —CH₂—C(O)—N(R¹)₂, —CH₂—S(O)(R¹),        —CH₂—S(O)₂(R¹), —CH₂—CH(OC(O)CH₂R¹)—CH₂(OC(O)CH₂R¹),        cholesteryl, enolpyruvate (HOOC—C(═CH₂)—), glycerol;    -   a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide        (3 to 9 monosaccharide residues);    -   triglycerides such as α-D-β-diglycerides (wherein the fatty        acids composing glyceride lipids generally are naturally        occurring saturated or unsaturated C₆₋₂₆, C₆₋₁₈ or C₆₋₁₀ fatty        acids such as linoleic, lauric, myristic, palmitic, stearic,        oleic, palmitoleic, linolenic and the like fatty acids) linked        to acyl of the parental compounds herein through a glyceryl        oxygen of the triglyceride;    -   phospholipids linked to the carboxyl group through the phosphate        of the phospholipid;    -   phthalidyl (shown in FIG. 1 of Clayton et al., Antimicrob.        Agents Chemo. (1974) 5(6):670-671;    -   cyclic carbonates such as (5-R_(d)-2-oxo-1,3-dioxolen-4-yl)        methyl esters (Sakamoto et al., Chem. Pharm. Bull. (1984)        32(6)2241-2248) where R_(d) is R₁, R⁴ or aryl; and

The hydroxyl groups of the compounds of this invention optionally aresubstituted with one of groups III, IV or V disclosed in WO 94/21604, orwith isopropyl.

Table A lists examples of protecting group ester moieties that forexample can be bonded via oxygen to —C(O)O— and —P(O)(O—)₂ groups.Several amidates also are shown, which are bound directly to —C(O)— or—P(O)₂. Esters of structures 1-5,8-10 and 16, 17, 19-22 are synthesizedby reacting the compound herein having a free hydroxyl with thecorresponding halide (chloride or acyl chloride and the like) andN,N-dicyclohexyl-N-morpholine carboxamidine (or another base such asDBU, triethylamine, CsCO₃, N,N-dimethylaniline and the like) in DMF (orother solvent such as acetonitrile or N-methylpyrrolidone). When thecompound to be protected is a phosphonate, the esters of structures 5-7,11, 12, 21, and 23-26 are synthesized by reaction of the alcohol oralkoxide salt (or the corresponding amines in the case of compounds suchas 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate(or another activated phosphonate). TABLE A 1. —CH₂—C(O)—N(R₁)₂* 2.—CH₂—S(O)(R₁) 3. —CH₂—S(O)₂(R₁) 4. —CH₂—O—C(O)—CH₂—C₆H₅ 5. 3-cholesteryl6. 3-pyridyl 7. N-ethylmorpholino 8. —CH₂—O—C(O)—C₆H₅ 9.—CH₂—O—C(O)—CH₂CH₃ 10. —CH₂—O—C(O)—C(CH₃)₃ 11. —CH₂—CCl₃ 12. —C₆H₅ 13.—NH—CH₂—C(O)O—CH₂CH₃ 14. —N(CH₃)—CH₂—C(O)O—CH₂CH₃ 15. —NHR₁ 16.—CH₂—O—C(O)—C₁₀H₁₅ 17. —CH₂—O—C(O)—CH(CH₃)₂ 18.—CH₂—C#H(OC(O)CH₂R₁)—CH₂— —(OC(O)CH₂R₁)* 19.

20.

21.

22.

23.

24.

25.

26

#chiral center is (R), (S) or racemate.

Other esters that are suitable for use herein are described in EP632048.

Protecting groups also includes “double ester” formingprofunctionalities such as —CH₂OC(O)OCH₃,

—CH₂SCOCH₃, —CH₂OCON(CH₃)₂, or alkyl- or aryl-acyloxyalkyl groups of thestructure —CH(R¹ or W⁵)O((CO)R³⁷) or —CH(R¹ or W⁵)((CO)OR³⁸) (linked tooxygen of the acidic group) wherein R³⁷ and R³⁸ are alkyl, aryl, oralkylaryl groups (see U.S. Pat. No. 4,968,788). Frequently R³⁷ and R³⁸are bulky groups such as branched alkyl, ortho-substituted aryl,meta-substituted aryl, or combinations thereof, including normal,secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example isthe pivaloyloxymethyl group. These are of particular use with prodrugsfor oral administration. Examples of such useful protecting groups arealkylacyloxymethyl esters and their derivatives, including—CH(CH₂CH₂OCH₃)OC(O)C(CH₃)₃,

—CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)C(CH₃)₃, —CH(CH₂OCH₃)OC(O)C(CH₃)₃,—CH(CH(CH₃)₂)OC(O)C(CH₃)₃, —CH₂OC(O)CH₂CH(CH₃)₂, —CH₂OC(O)C₆H₁₁,—CH₂OC(O)C₆H₅, —CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)CH₂CH₃, —CH₂OC(O)CH(CH₃)₂,—CH₂OC(O)C(CH₃)₃ and —CH₂OC(O)CH₂C₆H₅.

In some claims the protected acidic group is an ester of the acidicgroup and is the residue of a hydroxyl-containing functionality. Inother claims, an amino compound is used to protect the acidfunctionality. The residues of suitable hydroxyl or amino-containingfunctionalities are set forth above or are found in WO 95/07920. Ofparticular interest are the residues of amino acids, amino acid esters,polypeptides, or aryl alcohols. Typical amino acid, polypeptide andcarboxyl-esterified amino acid residues are described on pages 11-18 andrelated text of WO 95/07920 as groups L1 or L2. WO 95/07920 expresslyteaches the amidates of phosphonic acids, but it will be understood thatsuch amidates are formed with any of the acid groups set forth hereinand the amino acid residues set forth in WO 95/07920.

Typical esters for protecting acidic functionalities are also describedin WO 95/07920, again understanding that the same esters can be formedwith the acidic groups herein as with the phosphonate of the '920publication. Typical ester groups are defined at least on WO 95/07920pages 89-93 (under R³¹ or R³⁵), the table on page 105, and pages 21-23(as R). Of particular interest are esters of unsubstituted aryl such asphenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy-and/or alkylestercarboxy-substituted aryl or alkylaryl, especiallyphenyl, ortho-ethoxyphenyl, or C₁-C₄ alkylestercarboxyphenyl (salicylateC₁-C₁₂ alkylesters).

The protected acidic groups, particularly when using the esters oramides of WO 95/07920, are useful as prodrugs for oral administration.However, it is not essential that the acidic group be protected in orderfor the compounds of this invention to be effectively administered bythe oral route. When the compounds of the invention having protectedgroups, in particular amino acid amidates or substituted andunsubstituted aryl esters are administered systemically or orally theyare capable of hydrolytic cleavage in vivo to yield the free acid.

One or more of the acidic hydroxyls are protected. If more than oneacidic hydroxyl is protected then the same or a different protectinggroup is employed, e.g., the esters may be different or the same, or amixed amidate and ester may be used.

Typical hydroxy protecting groups described in Greene (pages 14-118)include substituted methyl and alkyl ethers, substituted benzyl ethers,silyl ethers, esters including sulfonic acid esters, and carbonates. Forexample:

-   -   Ethers (methyl, t-butyl, allyl);    -   Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl,        t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl,        Benzyloxymethyl, p-Methoxybenzyloxymethyl,        (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl,        4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl,        2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl,        2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl,        3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,        1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,        4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl        S,S-Dioxido,        1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,        1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,        2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));    -   Substituted Ethyl Ethers (1-Ethoxyethyl,        1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl,        1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl,        2,2,2-Trichloroethyl, 2-Trimethylsilylethyl,        2-(Phenylselenyl)ethyl,    -   p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);    -   Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl,        o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl,        p-Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl,        3-Methyl-2-picolyl N-Oxido, Diphenylmethyl,        p,p′-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl,        α-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,        Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl,        4-(4′-Bromophenacyloxy)phenyldiphenylmethyl,        4,4′,4″-Tris(4,5-dichlorophthalimidophenyl)methyl,        4,4′,4″-Tris(levulinoyloxyphenyl)methyl,        4,4′,4″-Tris(benzoyloxyphenyl)methyl,        3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,        1,1-Bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-Anthryl,        9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,        1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido);    -   Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,        Dimethylisopropylsilyl, Diethylisopropylsilyl,        Dimethylthexylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl,        Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl,        Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl);    -   Esters (Formate, Benzoylformate, Acetate, Choroacetate,        Dichloroacetate, Trichloroacetate, Trifluoroacetate,        Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,        p-Chlorophenoxyacetate, p-poly-Phenylacetate,        3-Phenylpropionate, 4-Oxopentanoate (Levulinate),        4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate,        Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,        2,4,6-Trimethylbenzoate (Mesitoate));    -   Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl,        2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,        2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl,        Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl,        3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl        Thiocarbonate, 4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate);    -   Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate,        4-Nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate,        2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate,        4-(Methylthiomethoxy)butyrate,        2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters        (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3        tetramethylbutyl)phenoxyacetate,        2,4-Bis(1,1-dimethylpropyl)phenoxyacetate,        Chlorodiphenylacetate, Isobutyrate, Monosuccinate,        (E)-2-Methyl-2-butenoate (Tigloate),        o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate,        Nitrate, Alkyl N,N,N′,N′-Tetramethylphosphorodiamidate,        N-Phenylcarbamate, Borate, Dimethylphosphinothioyl,        2,4-Dinitrophenylsulfenate); and    -   Sulfonates (Sulfate, Methanesulfonate (Mesylate),        Benzylsulfonate, Tosylate).

Typical 1,2-diol protecting groups (thus, generally where two OH groupsare taken together with the protecting functionality) are described inGreene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

More typically, 1,2-diol protecting groups include those shown in TableB, still more typically, epoxides, acetonides, cyclic ketals and arylacetals. TABLE B

wherein R⁹ is C₁-C₆ alkyl.Amino Protecting Groups

Another set of protecting groups include any of the typical aminoprotecting groups described by Greene at pages 315-385. They include:

-   -   Carbamates: (methyl and ethyl, 9-fluorenylmethyl,        9(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,        2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,        4-methoxyphenacyl);    -   Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl,        2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,        1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,        1,1-dimethyl-2,2,2-trichloroethyl,        1-methyl-1-(4-biphenylyl)ethyl,        1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and        4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,        1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,        4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,        benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,        p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,        9-anthrylmethyl, diphenylmethyl);    -   Groups With Assisted Cleavage: (2-methylthioethyl,        2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,        [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,        2,4-dimethylthiophenyl, 2-phosphonioethyl,        2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,        m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,        5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl);    -   Groups Capable of Photolytic Cleavage: (m-nitrophenyl,        3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,        phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives        (phenothiazinyl-(10)-carbonyl,        N′-p-toluenesulfonylaminocarbonyl, N′-phenylaminothiocarbonyl);    -   Miscellaneous Carbamates: (t-amyl, S-benzyl thiocarbamate,        p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,        cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,        2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,        1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,        1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,        2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl,        p-(p′-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,        1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,        1-methyl-1-(3,5-dimethoxyphenyl)ethyl,        1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,        1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,        2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,        2,4,6-trimethylbenzyl);    -   Amides: (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl,        N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,        N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl,        N-benzoyl, N-p-phenylbenzoyl);    -   Amides With Assisted Cleavage: (N-o-nitrophenylacetyl,        N-o-nitrophenoxyacetyl, N-acetoacetyl,        (N′-dithiobenzyloxycarbonylamino)acetyl,        N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,        N-2-methyl-2-(o-nitrophenoxy)propionyl,        N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,        N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl,        N-acetylmethionine, N-o-nitrobenzoyl,        N-o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one);    -   Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl,        N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,        N-1,1,4,4-tetramethyldisilylazacyclopentane adduct,        5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,        5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexan-2-one,        1-substituted 3,5-dinitro-4-pyridonyl);    -   N-Alkyl and N-Aryl Amines: (N-methyl, N-allyl,        N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,        N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary        Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl,        N-5-dibenzosuberyl, N-triphenylmethyl,        N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,        N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl,        N-2-picolylamine N-oxide);    -   Imine Derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene,        N-p-methoxybenylidene, N-diphenylmethylene,        N-[(2-pyridyl)mesityl]methylene,        N,(N′,N′-dimethylaminomethylene, N,N-isopropylidene,        N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,        N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene);    -   Enamine Derivatives: (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl));    -   N-Metal Derivatives (N-borane derivatives, N-diphenylborinic        acid derivatives, N-[phenyl(pentacarbonylchromium- or        -tungsten)]carbenyl, N-copper or N-zinc chelate);    -   N—N Derivatives: (N-nitro, N-nitroso, N-oxide);    -   N—P Derivatives: (N-diphenylphosphinyl,        N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl        phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl);    -   N—Si Derivatives, N—S Derivatives, and N-Sulfenyl Derivatives:        (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,        N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,        N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,        N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives        (N-p-toluenesulfonyl, N-benzenesulfonyl,        N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,        N-2,4,6-trimethoxybenzenesulfonyl,        N-2,6-dimethyl-4-methoxybenzenesulfonyl,        N-pentamethylbenzenesulfonyl,        N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,        N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,        N-2,6-dimethoxy-4-methylbenzenesulfonyl,        N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,        N-f-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,        N-4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonyl,        N-benzylsulfonyl, N-trifluoromethylsulfonyl,        N-phenacylsulfonyl).

More typically, protected amino groups include carbamates and amides,still more typically, —NHC(O)R¹ or —N═CR¹N(R¹)₂. Another protectinggroup, also useful as a prodrug for amino or —NH(R⁵), is:

See for example Alexander, J. et al. (1996) J. Med. Chem. 39:480-486.Amino Acid and Polypeptide Protecting Group and Conjugates

An amino acid or polypeptide protecting group of a compound of theinvention has the structure R¹⁵NHCH(R¹⁶)C(O)—, where R¹⁵ is H, an aminoacid or polypeptide residue, or R⁵, and R¹⁶ is defined below.

R¹⁶ is lower alkyl or lower alkyl (C₁-C₆) substituted with amino,carboxyl, amide, carboxyl ester, hydroxyl, C₆-C₇ aryl, guanidinyl,imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R¹⁰also is taken together with the amino acid α N to form a proline residue(R¹⁰=—CH₂)₃—). However, R¹⁰ is generally the side group of anaturally-occurring amino acid such as H, —CH₃, —CH(CH₃)₂,—CH₂—CH(CH₃)₂, —CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH,—CH(OH)—CH₃, —CH₂—SH, —CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂,—CH₂—COOH, —CH₂—CH₂—COOH, —(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R¹⁰also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl,imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Another set of protecting groups include the residue of anamino-containing compound, in particular an amino acid, a polypeptide, aprotecting group, —NHSO₂R, NHC(O)R, —N(R)₂, NH₂ or —NH(R)(H), wherebyfor example a carboxylic acid is reacted, i.e. coupled, with the amineto form an amide, as in C(O)NR₂. A phosphonic acid may be reacted withthe amine to form a phosphonamidate, as in —P(O)(OR)(NR₂).

In general, amino acids have the structure R¹⁷C(O)CH(R¹⁶)NH—, where R¹⁷is —OH, —OR, an amino acid or a polypeptide residue. Amino acids are lowmolecular weight compounds, on the order of less than about 1000 MW andwhich contain at least one amino or imino group and at least onecarboxyl group. Generally the amino acids will be found in nature, i.e.,can be detected in biological material such as bacteria or othermicrobes, plants, animals or man. Suitable amino acids typically arealpha amino acids, i.e. compounds characterized by one amino or iminonitrogen atom separated from the carbon atom of one carboxyl group by asingle substituted or unsubstituted alpha carbon atom. Of particularinterest are hydrophobic residues such as mono- or di-alkyl or arylamino acids, cycloalkylamino acids and the like. These residuescontribute to cell permeability by increasing the partition coefficientof the parental drug. Typically, the residue does not contain asulfhydryl or guanidino substituent.

Naturally-occurring amino acid residues are those residues foundnaturally in plants, animals or microbes, especially proteins thereof.Polypeptides most typically will be substantially composed of suchnaturally-occurring amino acid residues. These amino acids are glycine,alanine, valine, leucine, isoleucine, serine, threonine, cysteine,methionine, glutamic acid, aspartic acid, lysine, hydroxylysine,arginine, histidine, phenylalanine, tyrosine, tryptophan, proline,asparagine, glutamine and hydroxyproline. Additionally, unnatural aminoacids, for example, valanine, phenylglycine and homoarginine are alsoincluded. Commonly encountered amino acids that are not gene-encoded mayalso be used in the present invention. All of the amino acids used inthe present invention may be either the D- or L-optical isomer. Inaddition, other peptidomimetics are also useful in the presentinvention. For a general review, see Spatola, A. F., in Chemistry andBiochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds.,Marcel Dekker, New York, p. 267 (1983).

When protecting groups are single amino acid residues or polypeptidesthey optionally are substituted at R³ of substituents A¹, A² or A³ inFormula I. These conjugates are produced by forming an amide bondbetween a carboxyl group of the amino acid (or C-terminal amino acid ofa polypeptide for example). Similarly, conjugates are formed between R³(Formula I) and an amino group of an amino acid or polypeptide.Generally, only one of any site in the parental molecule is amidatedwith an amino acid as described herein, although it is within the scopeof this invention to introduce amino acids at more than one permittedsite. Usually, a carboxyl group of R³ is amidated with an amino acid. Ingeneral, the α-amino or α-carboxyl group of the amino acid or theterminal amino or carboxyl group of a polypeptide are bonded to theparental functionalities, i.e., carboxyl or amino groups in the aminoacid side chains generally are not used to form the amide bonds with theparental compound (although these groups may need to be protected duringsynthesis of the conjugates as described further below).

With respect to the carboxyl-containing side chains of amino acids orpolypeptides it will be understood that the carboxyl group optionallywill be blocked, e.g., by R¹, esterified with R⁵ or amidated. Similarly,the amino side chains R¹⁶ optionally will be blocked with R¹ orsubstituted with R⁵.

Such ester or amide bonds with side chain amino or carboxyl groups, likethe esters or amides with the parental molecule, optionally arehydrolyzable in vivo or in vitro under acidic (pH <3) or basic (pH >10)conditions. Alternatively, they are substantially stable in thegastrointestinal tract of humans but are hydrolyzed enzymatically inblood or in intracellular environments. The esters or amino acid orpolypeptide amidates also are useful as intermediates for thepreparation of the parental molecule containing free amino or carboxylgroups. The free acid or base of the parental compound, for example, isreadily formed from the esters or amino acid or polypeptide conjugatesof this invention by conventional hydrolysis procedures.

When an amino acid residue contains one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates, scalematesor mixtures thereof may be used. In general, if the intermediates are tobe hydrolyzed non-enzymatically (as would be the case where the amidesare used as chemical intermediates for the free acids or free amines), Disomers are useful. On the other hand, L isomers are more versatilesince they can be susceptible to both non-enzymatic and enzymatichydrolysis, and are more efficiently transported by amino acid ordipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R^(x)or R^(y) include the following:

-   -   Glycine;    -   Aminopolycarboxylic acids, e.g., aspartic acid,        β-hydroxyaspartic acid, glutamic acid, β-hydroxyglutamic acid,        β-methylaspartic acid, β-methylglutamic acid,        β,β-dimethylaspartic acid, γ-hydroxyglutamic acid,        β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,        γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic        acid, 2-aminosuberic acid and 2-aminosebacic acid;    -   Amino acid amides such as glutamine and asparagine;    -   Polyamino- or polybasic-monocarboxylic acids such as arginine,        lysine, β-aminoalanine, γ-aminobutyrine, ornithine, citruline,        homoarginine, homocitrulline, hydroxylysine, allohydroxylsine        and diaminobutyric acid;    -   Other basic amino acid residues such as histidine;    -   Diaminodicarboxylic acids such as α,α′-diaminosuccinic acid,        α,α′-diaminoglutaric acid, α,α′-diaminoadipic acid,        α,α′-diaminopimelic acid, α,α′-diamino-β-hydroxypimelic acid,        α,α′-diaminosuberic acid, α,α′-diaminoazelaic acid, and        α,α′-diaminosebacic acid;    -   Imino acids such as proline, hydroxyproline, allohydroxyproline,        γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid, and        azetidine-2-carboxylic acid;    -   A mono- or di-alkyl (typically C₁-C₈ branched or normal) amino        acid such as alanine, valine, leucine, allylglycine, butyrine,        norvaline, norleucine, heptyline, α-methylserine,        α-amino-α-methyl-γ-hydroxyvaleric acid,        α-amino-α-methyl-δ-hydroxyvaleric acid,        α-amino-α-methyl-ε-hydroxycaproic acid, isovaline,        α-methylglutamic acid, α-aminoisobutyric acid,        α-aminodiethylacetic acid, α-aminodiisopropylacetic acid,        α-aminodi-n-propylacetic acid, α-aminodiisobutylacetic acid,        α-aminodi-n-butylacetic acid, α-aminoethylisopropylacetic acid,        α-amino-n-propylacetic acid, α-aminodiisoamyacetic acid,        α-methylaspartic acid, α-methylglutamic acid,        1-aminocyclopropane-1-carboxylic acid, isoleucine,        alloisoleucine, tert-leucine, β-methyltryptophan and        α-amino-β-ethyl-β-phenylpropionic acid;    -   β-phenylserinyl;    -   Aliphatic α-amino-β-hydroxy acids such as serine,        β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline, and        α-amino-β-hydroxystearic acid;    -   α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine,        δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine        residues; canavine and canaline; γ-hydroxyomithine;    -   2-hexosaminic acids such as D-glucosaminic acid or        D-galactosaminic acid;    -   α-Amino-δ-thiols such as penicillamine, β-thiolnorvaline or        β-thiolbutyrine;    -   Other sulfur containing amino acid residues including cysteine;        homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteine        sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of        cysteine or homocysteine;    -   Phenylalanine, tryptophan and ring-substituted α-amino acids        such as the phenyl- or cyclohexylamino acids α-aminophenylacetic        acid, α-aminocyclohexylacetic acid and        α-amino-β-cyclohexylpropionic acid; phenylalanine analogues and        derivatives comprising aryl, lower alkyl, hydroxy, guanidino,        oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g.,        tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro,        o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-,        2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-,        pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and        tryptophan analogues and derivatives including kynurenine,        3-hydroxykynurenine, 2-hydroxytryptophan and        4-carboxytryptophan;    -   α-Amino substituted amino acids including sarcosine        (N-methylglycine), N-benzylglycine, N-methylalanine,        N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine,        N-methylvaline and N-benzylvaline; and    -   α-Hydroxy and substituted α-hydroxy amino acids including        serine, threonine, allothreonine, phosphoserine and        phosphothreonine.

Polypeptides are polymers of amino acids in which a carboxyl group ofone amino acid monomer is bonded to an amino or imino group of the nextamino acid monomer by an amide bond. Polypeptides include dipeptides,low molecular weight polypeptides (about 1500-5000 MW) and proteins.Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, andsuitably are substantially sequence-homologous with human, animal, plantor microbial proteins. They include enzymes (e.g., hydrogen peroxidase)as well as immunogens such as KLH, or antibodies or proteins of any typeagainst which one wishes to raise an immune response. The nature andidentity of the polypeptide may vary widely.

The polypeptide amidates are useful as immunogens in raising antibodiesagainst either the polypeptide (if it is not immunogenic in the animalto which it is administered) or against the epitopes on the remainder ofthe compound of this invention.

Antibodies capable of binding to the parental non-peptidyl compound areused to separate the parental compound from mixtures, for example indiagnosis or manufacturing of the parental compound. The conjugates ofparental compound and polypeptide generally are more immunogenic thanthe polypeptides in closely homologous animals, and therefore make thepolypeptide more immunogenic for facilitating raising antibodies againstit. Accordingly, the polypeptide or protein may not need to beimmunogenic in an animal typically used to raise antibodies, e.g.,rabbit, mouse, horse, or rat, but the final product conjugate should beimmunogenic in at least one of such animals. The polypeptide optionallycontains a peptidolytic enzyme cleavage site at the peptide bond betweenthe first and second residues adjacent to the acidic heteroatom. Suchcleavage sites are flanked by enzymatic recognition structures, e.g., aparticular sequence of residues recognized by a peptidolytic enzyme.

Peptidolytic enzymes for cleaving the polypeptide conjugates of thisinvention are well known, and in particular include carboxypeptidases.Carboxypeptidases digest polypeptides by removing C-terminal residues,and are specific in many instances for particular C-terminal sequences.Such enzymes and their substrate requirements in general are well known.For example, a dipeptide (having a given pair of residues and a freecarboxyl terminus) is covalently bonded through its α-amino group to thephosphorus or carbon atoms of the compounds herein. In claims where W₁is phosphonate it is expected that this peptide will be cleaved by theappropriate peptidolytic enzyme, leaving the carboxyl of the proximalamino acid residue to autocatalytically cleave the phosphonoamidatebond.

Suitable dipeptidyl groups (designated by their single letter code) areAA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW,AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS,RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF,NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK,DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI,CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG,EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE,QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD,GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR,HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV,IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW,IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS,LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF,KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK,MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI,FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG,PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE,SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD,TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR,WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV,YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW,YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS,VT, VW, VY and VV.

Tripeptide residues are also useful as protecting groups. When aphosphonate is to be protected, the sequence —X⁴-pro-X⁵— (where X⁴ isany amino acid residue and X⁵ is an amino acid residue, a carboxyl esterof proline, or hydrogen) will be cleaved by luminal carboxypeptidase toyield X⁴ with a free carboxyl, which in turn is expected toautocatalytically cleave the phosphonoamidate bond. The carboxy group ofX⁵ optionally is esterified with benzyl.

Dipeptide or tripeptide species can be selected on the basis of knowntransport properties and/or susceptibility to peptidases that can affecttransport to intestinal mucosal or other cell types. Dipeptides andtripeptides lacking an α-amino group are transport substrates for thepeptide transporter found in brush border membrane of intestinal mucosalcells (Bai, J. P. F., (1992) Pharm Res. 9:969-978). Transport competentpeptides can thus be used to enhance bioavailability of the amidatecompounds. Di- or tripeptides having one or more amino acids in the Dconfiguration are also compatible with peptide transport and can beutilized in the amidate compounds of this invention. Amino acids in theD configuration can be used to reduce the susceptibility of a di- ortripeptide to hydrolysis by proteases common to the brush border such asaminopeptidase N. In addition, di- or tripeptides alternatively areselected on the basis of their relative resistance to hydrolysis byproteases found in the lumen of the intestine. For example, tripeptidesor polypeptides lacking asp and/or glu are poor substrates foraminopeptidase A, di- or tripeptides lacking amino acid residues on theN-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) arepoor substrates for endopeptidase, and peptides lacking a pro residue atthe penultimate position at a free carboxyl terminus are poor substratesfor carboxypeptidase P. Similar considerations can also be applied tothe selection of peptides that are either relatively resistant orrelatively susceptible to hydrolysis by cytosolic, renal, hepatic, serumor other peptidases. Such poorly cleaved polypeptide amidates areimmunogens or are useful for bonding to proteins in order to prepareimmunogens.

Specific Embodiments of the Invention

Specific values described for radicals, substituents, and ranges, aswell as specific embodiments of the invention described herein, are forillustration only; they do not exclude other defined values or othervalues within defined ranges.

In one specific embodiment of the invention, the conjugate is a compoundthat is substituted with one or more phosphonate groups either directlyor indirectly through a linker; and that is optionally substituted withone or more groups A⁰; or a pharmaceutically acceptable salt thereof,wherein:

-   -   A⁰ is A¹, A² or W³;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

-   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),    N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or    —S(O)_(M2)—S(O)_(M2)—; R^(x) is independently H, R¹, W³, a    protecting group, or the formula:    -   wherein:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R¹ is independently H or alkyl of 1 to 18 carbon atoms;    -   R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is        independently substituted with 0 to 3 R³ groups or taken        together at a carbon atom, two R² groups form a ring of 3 to 8        carbons and the ring may be substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),        —N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   R^(5a) is independently alkylene of 1 to 18 carbon atoms,        alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon        atoms any one of which alkylene, alkenylene or alkynylene is        substituted with 0-3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;    -   M2 is 0, 1 or 2;    -   M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

and W^(5a) is a carbocycle or a heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups. A specific velue forM12a is 1.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the A¹ is of the formula:

In another specific embodiment of the A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups;

In another specific embodiment of the A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups;

-   -   In another specific embodiment of the A¹ is of the formula:        wherein W^(5a) is a carbocycle or heterocycle where W^(5a) is        independently substituted with 0 or 1 R² groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In a specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In another specific embodiment of the invention e M12b is 0, Y² is abond and W⁵ is a carbocycle or heterocycle where W⁵ is optionally andindependently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention A² is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) is optionallyand independently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention M12a is 1.

In another specific embodiment of the invention A² is selected fromphenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl andsubstituted pyridyl.

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In a specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention M12d is 1.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is a carbocycle.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is phenyl.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention R¹ is H.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wheren Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A ³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A ³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

wherein: Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In a specific embodiment of the invention A⁰ is of the formula:

wherein each R is independently (C₁-C₆)alkyl.

In a specific embodiment of the invention R^(x) is independently H, R¹,W³, a protecting group, or the formula:

-   -   wherein:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R¹ is independently H or alkyl of 1 to 18 carbon atoms;    -   R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is        independently substituted with 0 to 3 R³ groups or taken        together at a carbon atom, two R² groups form a ring of 3 to 8        carbons and the ring may be substituted with 0 to 3 R³ groups;    -   In a specific embodiment of the invention R^(x) is of the        formula:        wherein Y^(1a) is O or S; and Y^(2c) is O, N(R^(y)) or S.

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2d) is O or N(R^(y)).

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(y) is hydrogen or alkyl of1 to 10 carbons.

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention Y¹ is O or S

In a specific embodiment of the invention Y² is O, N(R^(y)) or S.

In one specific embodiment of the invention R^(x) is a group of theformula:

wherein:

-   -   m1a, m1b, m1c, m1d and m1e are independently 0 or 1;    -   m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   R^(y) is H, W³, R² or a protecting group; provided that:    -   if m1a, m12c, and mid are 0, then m1b, m1c and m1e are 0;    -   if m1a and m12c are 0 and mid is not 0, then m1b and m1c are 0;    -   if m1a and mid are 0 and m12c is not 0, then m1b and at least        one of m1c and m/e are 0;    -   if m1a is 0 and m12c and mid are not 0, then m1b is 0;    -   if m12c and mid are 0 and m1a is not 0, then at least two of        m1b, m1c and m1e are 0;    -   if m12c is 0 and m1a and mid are not 0, then at least one of m1b        and m1c are 0; and    -   if m1d is 0 and m1a and m12c are not 0, then at least one of m1c        and m1e are 0.

In another specific embodiment, the invention provides a compound of theformula:[DRUG]-(A⁰)_(nn)

-   -   or a pharmaceutically acceptable salt thereof wherein,    -   DRUG is a compound of any one of formulae 500-611    -   nn is 1, 2, or 3;    -   A⁰ is A¹, A² or W³ with the proviso that the compound includes        at least one A¹;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));    -   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or        —S(O)_(M2)—S(O)_(M2)—;    -   R^(x) is independently H, R¹, W³, a protecting group, or the        formula:    -   wherein:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R¹ is independently H or alkyl of 1 to 18 carbon atoms;    -   R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is        independently substituted with 0 to 3 R³ groups or taken        together at a carbon atom, two R² groups form a ring of 3 to 8        carbons and the ring may be substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),        —N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   R^(5a) is independently alkylene of 1 to 18 carbon atoms,        alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon        atoms any one of which alkylene, alkenylene or alkynylene is        substituted with 0-3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;    -   M2 is 0, 1 or 2;    -   M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M1a, M1c, and M1d are independently 0 or 1;    -   M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   X⁶⁶ is hydrogen or fluorine; and    -   X⁶⁷ is hydrogen, hydroxy, or acyloxy.

In another specific embodiment, the invention provides a compound of theformula 1-296;

-   -   or a pharmaceutically acceptable salt thereof wherein:    -   A⁰ is A¹;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));    -   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or        —S(O)_(M2)—S(O)_(M2)—;    -   R^(x) is independently H, W³, a protecting group, or the        formula:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R¹ is independently H or alkyl of 1 to 18 carbon atoms;    -   R² is independently H, R³ or R⁴ wherein each R⁴ is independently        substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),        —N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   R^(5a) is independently alkylene of 1 to 18 carbon atoms,        alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon        atoms any one of which alkylene, alkenylene or alkynylene is        substituted with 0-3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y)W⁵, —SO₂R⁵, or —SO₂W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;    -   M2 is 0, 1 or 2;    -   M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M1a, M1c, and M1d are independently 0 or 1;    -   M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   X⁵⁰ is H or F;    -   X⁵¹ is H, hydroxy, or acyloxy;    -   X⁵² is NH₂ or EtC(O)N—Na+;    -   X⁵³ is H, methyl, CF₃, or halo;    -   X⁵⁴ is H, halo, trifluoromethyl, (C1-C3)alkyl, cyano, or        (C₁-C₃)alkoxy;    -   X⁵⁵ is H, F, Cl, Br, methyl, or trifluoromethyl;    -   X⁵⁶ is hydrogen, halo, trifluoromethyl, cyano, methyl;    -   X⁵⁷ is H, F, Cl, CF₃, cyano, methyl, or t-butyl;    -   X⁵⁸ is H or CH₂OH;    -   X⁵⁹ is H or F;    -   X⁶⁰ is H, trifluoromethyl, or cyano;    -   X⁶¹ is methoxy, ethoxy, vinyl, ethyl, methyl, cyclopropyl,        N-methylamino, or N-formylamino;    -   X⁶² is methyl, chloro, or trifluoromethyl;    -   X⁶³ is H, methyl, ethyl, cyclopropyl, vinyl, or trifluoromethyl;    -   X⁶⁴ is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl,        3-methyl-1-buten-1yl;    -   X⁶⁵ is H or F; and    -   Ar is aryl or heteroaryl.

In another specific embodiment, the invention provides a compound of theformula:[DRUG]-[L-P(═Y¹)—Y²—R^(x)]_(nn)

-   -   or a pharmaceutically acceptable salt thereof wherein,    -   DRUG is a compound of any one of 500-611;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));    -   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or        —S(O)_(M2)—S(O)_(M2)—;    -   R^(x) is independently H, W³, a protecting group, or the        formula:    -   R^(y) is independently H, W³, R² or a protecting group;    -   R² is independently H, R³ or R⁴ wherein each R⁴ is independently        substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y)R^(x),        —N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   M2 is 1, 2, or 3;    -   M1a, M1c, and M1d are independently 0 or 1;    -   M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   X⁶⁶ is hydrogen or fluorine; and    -   X⁶⁷ is hydrogen, hydroxy, or acyloxy;    -   nn is 1, 2, or 3; and    -   L is a linking group.

In another specific embodiment, the invention provides a compound ofwhich is a compound of the formula:[DRUG]-(A⁰)_(nn)or a pharmaceutically acceptable salt thereof wherein,

-   -   DRUG is a compound of any one of formulae 500-611;    -   nn is 1, 2, or 3;    -   A⁰ is A¹, A², or W³ with the proviso that the compound includes        at least one A¹;    -   Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), or N(N(R^(x))(R^(x)));    -   Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),        N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or        —S(O)_(M2)—S(O)_(M2)—;    -   R^(x) is independently H, W³, a protecting group, or the        formula:

R^(y) is independently H, W³, R² or a protecting group;

-   -   R² is independently H, R³ or R⁴ wherein each R⁴ is independently        substituted with 0 to 3 R³ groups;    -   R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is        bound to a heteroatom, then R³ is R^(3c) or R^(3d);    -   R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;    -   R^(3b) is Y¹;    -   R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x),        —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),        —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),        —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),        N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));    -   R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));    -   R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18        carbon atoms, or alkynyl of 2 to 18 carbon atoms;    -   R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;    -   W³ is W⁴ or W⁵;    -   W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;    -   W⁵ is carbocycle or heterocycle wherein W⁵ is independently        substituted with 0 to 3 R² groups;    -   W⁶ is W³ independently substituted with 1, 2, or 3 A groups;    -   M2 is 0, 1 or 2;    -   M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   M1a, M1c, and M1d are independently 0 or 1;    -   M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;    -   X⁶⁶ is hydrogen or fluorine; and    -   X⁶⁷ is hydrogen, hydroxy, or acyloxy.

In one specific embodiment of the invention X⁶¹ is methoxy, ethoxy,n-propoxy, difluoromethoxy, trifluoromethoxy, ethyl, methyl, propyl, orn-butyl)

In compounds of the invention W⁵ carbocycles and W⁵ heterocycles may beindependently substituted with 0 to 3 R² groups. W⁵ may be a saturated,unsaturated or aromatic ring comprising a mono- or bicyclic carbocycleor heterocycle. W⁵ may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.The W⁵ rings are saturated when containing 3 ring atoms, saturated ormono-unsaturated when containing 4 ring atoms, saturated, or mono- ordi-unsaturated when containing 5 ring atoms, and saturated, mono- ordi-unsaturated, or aromatic when containing 6 ring atoms.

A W⁵ heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or abicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P, and S). W⁵ heterocyclic monocyclesmay have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atomsand 1 to 2 heteroatoms selected from N and S). W⁵ heterocyclic bicycleshave 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6]system. The W⁵ heterocycle may be bonded to Y² through a carbon,nitrogen, sulfur or other atom by a stable covalent bond.

W⁵ heterocycles include for example, pyridyl, dihydropyridyl isomers,piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl,thiofuranyl, thienyl, and pyrrolyl. W⁵ also includes, but is not limitedto, examples such as:

W⁵ carbocycles and heterocycles may be independently substituted with 0to 3 R² groups, as defined above. For example, substituted W⁵carbocycles include:

Examples of substituted phenyl carbocycles include:

Linking Groups and Linkers

The invention provides conjugates that comprise an anti-inflammatorycompound that is linked to one or more phosphonate groups eitherdirectly (e.g. through a covalent bond) or through a linking group (i.e.a linker). The nature of the linker is not critical provided it does notinterfere with the ability of the phosphonate containing compound tofunction as a therapeutic agent. The phosphonate or the linker can belinked to the compound (e.g. a compound of 500-611) at any syntheticallyfeasible position on the compound by removing a hydrogen or any portionof the compound to provide an open valence for attachment of thephosphonate or the linker.

In one embodiment of the invention the linking group or linker (whichcan be designated “L”) can include all or a portions of the group A⁰,A¹, A², A³, or W³ described herein, such as for example, repeating unitsof alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino(e.g., polyethyleneamino, Jeffamine™); and diacid ester and amidesincluding succinate, succinamide, diglycolate, malonate, and caproamide.

In another embodiment of the invention the linking group or linker has amolecular weight of from about 20 daltons to about 400 daltons.

In another embodiment of the invention the linking group or linker has alength of about 5 angstroms to about 300 angstroms.

In another embodiment of the invention the linking group or linkerseparates the DRUG and the phosphorous of the phosphonate group by about5 angstroms to about 200 angstroms, inclusive, in length.

In another embodiment of the invention the linking group or linker is adivalent, branched or unbranched, saturated or unsaturated, hydrocarbonchain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2,3, or 4) of the carbon atoms is optionally replaced by (—O—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from (C₁-C₆)alkoxy,(C₃-C₆)Cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl, andheteroaryloxy.

In another embodiment of the invention the linking group or linker is ofthe formula W-A wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl,(C₂-C₂₄)alkynyl, (C₃-C₈)Cycloalkyl, (C₆-C₁₀)aryl or a combinationthereof, wherein W is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker is adivalent radical formed from a peptide.

In another embodiment of the invention the linking group or linker is adivalent radical formed from an amino acid.

In another embodiment of the invention the linking group or linker is adivalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine,poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine,poly-L-lysine or poly-L-lysine-L-tyrosine.

In another embodiment of the invention the linking group or linker is ofthe formula W—(CH₂)_(n) wherein, n is between about 1 and about 10; andW is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—,—S(O)₂—, —C(═O)—, —N(R)—, or a direct bond; wherein each R isindependently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker ismethylene, ethylene, or propylene.

In another embodiment of the invention the linking group or linker isattached to the phosphonate group through a carbon atom of the linker.

Intracellular Targeting

The phosphonate group of the compounds of the invention may cleave invivo in stages after they have reached the desired site of action, i.e.inside a cell. One mechanism of action inside a cell may entail a firstcleavage, e.g. by esterase, to provide a negatively-charged “locked-in”intermediate. Cleavage of a terminal ester grouping in a compound of theinvention thus affords an unstable intermediate which releases anegatively charged “locked in” intermediate.

After passage inside a cell, intracellular enzymatic cleavage ormodification of the phosphonate or prodrug compound may result in anintracellular accumulation of the cleaved or modified compound by a“trapping” mechanism. The cleaved or modified compound may then be“locked-in” the cell by a significant change in charge, polarity, orother physical property change which decreases the rate at which thecleaved or modified compound can exit the cell, relative to the rate atwhich it entered as the phosphonate prodrug. Other mechanisms by which atherapeutic effect are achieved may be operative as well. Enzymes whichare capable of an enzymatic activation mechanism with the phosphonateprodrug compounds of the invention include, but are not limited to,amidases, esterases, microbial enzymes, phospholipases, cholinesterases,and phosphatases.

From the foregoing, it will be apparent that many different drugs can bederivatized in accord with the present invention. Numerous such drugsare specifically mentioned herein. However, it should be understood thatthe discussion of drug families and their specific members forderivatization according to this invention is not intended to beexhaustive, but merely illustrative.

Anti-Inflammatory Compound

The compounds of the invention include those with anti-inflammatoryactivity. The compounds of the inventions bear one or more (e.g. 1, 2,3, or 4) phosphonate groups, which may be or may include a prodrugmoiety (e.g., a phosphonate diester, phosphonamidate-ester prodrug, or aphosphondiamidate-ester (Jiang et al., U.S. 2002/0173490 A1).

The term “anti-inflammatory compound” includes those compounds havinganti-inflammatory activity that are described in J. Org. Chem.64:1042-1044 (1999); J. Org. Chem. 64:1042-1044 (1999); U.S. Pat. No.4,335,121; U.S. Pat. No. 4,472,393; Tetrahedron, 1999, 55, 3355-3364; J.Pharm. Sci. 1985, 74, 365-374; U.S. Pat. No. 4,472,392; Drug Dev. Ind.Pharm., 1994, 20, 2479-2492; U.S. Pat. No. 3,312,590; Eur. J. Clin.Pharmacol. 1992, 43, 157-159; J. Am. Acad. Dermatol. 1993, 29, 576-580;U.S. Pat. No. 4,786,637; U.S. Pat. No. 4,753,935; Lee et al. Pharm Res,1990, 7, 161; U.S. Pat. No. 3,929,768; U.S. Pat. No. 4,680,299; U.S.Pat. No. 5,032,597; EP00184162A2; EP00184162A2; U.S. Pat. No. 3,929,992;U.S. Pat. No. 3,993,749; U.S. Pat. No. 4,873,259; and Biochemistry,2003, 42, 6057. The definition of anti-inflammatory compound includesnot only the generic disclosures cited above but also each and everyspecies set forth therein. The phosphonate group may be a phosphonateprodrug moiety. The prodrug moiety may be sensitive to hydrolysis, suchas, but not limited to, a pivaloyloxymethyl carbonate (POC) or POMgroup. Alternatively, the prodrug moiety may be sensitive to enzymaticpotentiated cleavage, such as a lactate ester or a phosphonamidate-estergroup.

The term “anti-inflammatory compound” also includes theophylline,methylxanthine, metamizole, rofecoxib, meloxicam, piroxicam, valdecoxib,tenoxicam, celecoxib, etodolac, etoricoxib, ibuprofin, naproxen,loxoprofen, diclofenac, relafen, mefenamic acid, nimesulide, aspirin,oxaprozin, toradol, R ketorolac, steroid phosphonates, pimecrolimus,everolimus, sirolimus, raltitrexed (tomudex), parecoxib, nimesulide,aminopterin, lumiracoxib, tacrolimus, prednisolone, rolipram, CC-1088,CDP 840, cilomilast, piclamilast, roflumilast, atizoram, VX-148,brequinar, diflunisal, doramapimod, tolfenamic acid, droxicam,flurbiprofen, indomethacin, lornoxicam, NCX-701,10-propargyl-10-deaza-aminopterin (PDX), talniflumate, thalidomide,dexketoprofen, zardaverine, nabumetone, licofelone, ketorolac, BCX-1777,amtolmetine guacil, aceclofenac, metoxibutropate, oxaprozin, sulindac,revimid, diprolene, aclometasone, hydrocortisone, vanceril, leflunomide,methylprednisolone suleptanate, prednisone, clobetasol, SMP-114,teriflunomide, salicylic acid, etoricoxib, L-791,943, halobetasolpropionate, ciclesonide, deflazacort, flunisolide, medroxyprogesterone,triamcinolone acetonide, rimexolone, fluticasone, mometasone furoate,methylprednisolone suleptanate, beclometasone, methylprednisoloneaceponate, merimepodib, mycophenolate, budesonide, dexamethasone,brequinar, immunosuppressive macrolide, methotrexate, zileuton, PNP-405,MDL-74428, prodrugs of 9-(3,3-dimethyl-5-phosphonopentyl) guanine,prodrugs of DADME-IMMG, leflunomide, zardaverine, cyclosporine A, andmizoribine.

Typically, compounds of the invention have a molecular weight of fromabout 400 amu to about 10,000 amu; in a specific embodiment of theinvention, compounds have a molecular weight of less than about 5000amu; in another specific embodiment of the invention, compounds have amolecular weight of less than about 2500 amu; in another specificembodiment of the invention, compounds have a molecular weight of lessthan about 1000 amu; in another specific embodiment of the invention,compounds have a molecular weight of less than about 800 amu; in anotherspecific embodiment of the invention, compounds have a molecular weightof less than about 600 amu; and in another specific embodiment of theinvention, compounds have a molecular weight of less than about 600 amuand a molecular weight of greater than about 400 amu.

The compounds of the invention also typically have a logD(polarity) lessthan about 5. In one embodiment the invention provides compounds havinga logD less than about 4; in another one embodiment the inventionprovides compounds having a logD less than about 3; in another oneembodiment the invention provides compounds having a logD greater thanabout −5; in another one embodiment the invention provides compoundshaving a logD greater than about −3; and in another one embodiment theinvention provides compounds having a logD greater than about 0 and lessthan about 3.

Selected substituents within the compounds of the invention are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. For example, R^(x) contains a R^(y)substituent. R^(y) can be R², which in turn can be R³. If R³ is selectedto be R^(3c), then a second instance of R^(x) can be selected. One ofordinary skill in the art of medicinal chemistry understands that thetotal number of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

By way of example and not limitation, W³, R^(y) and R³ are all recursivesubstituents in certain claims. Typically, each of these mayindependently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7,6, 5, 4, 3, 2, 1, or 0, times in a given claim. More typically, each ofthese may independently occur 12 or fewer times in a given claim. Moretypically yet, W³ will occur 0 to 8 times, R^(y) will occur 0 to 6 timesand R³ will occur 0 to 10 times in a given claim. Even more typically,W³ will occur 0 to 6 times, R^(y) will occur 0 to 4 times and R³ willoccur 0 to 8 times in a given claim.

Recursive substituents are an intended aspect of the invention. One ofordinary skill in the art of medicinal chemistry understands theversatility of such substituents. To the degree that recursivesubstituents are present in an claim of the invention, the total numberwill be determined as set forth above.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R¹” or “R^(6a)”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines indicate the site ofcovalent bond attachments to the adjoining groups, moieties, or atoms.

In one specific embodiment of the invention, the anti-inflammatorycompound is a non-steroidal anti-inflammatory compound (e.g. a compoundof formula 500-522, 525-565, 572-574, 579-583, 585-586, and 598-600 and602-611).

In another specific embodiment of the invention, the anti-inflammatorycompound is a steroidal anti-inflammatory compound. Steroidalanti-inflammatory compounds include those compounds that include thefollowing fused ring system:

In one embodiment of the invention, the anti-inflammatory compound is asteroidal anti-inflammatory compound that includes the following fusedring system:

In another embodiment of the invention, the anti-inflammatory compoundis a steroidal anti-inflammatory compound of any one of formulae523-524, 566-571, 575-578, 584, and 587-597, and 601.

In one embodiment of the invention, the compound is in an isolated andpurified form. Generally, the term “isolated and purified” means thatthe compound is substantially free from biological materials (e.g.blood, tissue, cells, etc.). In one specific embodiment of theinvention, the term means that the compound or conjugate of theinvention is at least about 50 wt. % free from biological materials; inanother specific embodiment, the term means that the compound orconjugate of the invention is at least about 75 wt. % free frombiological materials; in another specific embodiment, the term meansthat the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, theterm means that the compound or conjugate of the invention is at leastabout 98 wt. % free from biological materials; and in anotherembodiment, the term means that the compound or conjugate of theinvention is at least about 99 wt. % free from biological materials. Inanother specific embodiment, the invention provides a compound orconjugate of the invention that has been synthetically prepared (e.g.,ex vivo).

In one embodiment of the invention, the compound is not a purinenucleoside phosphorylase inhibitor; in one embodiment the compound isnot an anti-cancer agent; in one embodiment the compound is not activeagainst immune-mediated conditions; in one embodiment the compound isnot active against metabolic diseases the compound is not an antiviralagent; in one embodiment not a nucleoside; in one embodiment thecompound is not a kinase inhibitor; in one embodiment the compound isnot an antimetabolite; in one embodiment the compound is not an IMPDHinhibitor; in one embodiment the compound is not an anti-infective; inone embodiment the compound is not a compound of formula 242 or 243; inone embodiment the compound is not a compound of any one of formulae74-76, 199-203, 279-280, 204-210, and 286-292; in one embodiment thecompound is not a compound of any one of formulae 45-47, 56-58, 229,95-97, and 226-233; in one embodiment the compound is not a compound ofany one of formulae 82-85; in one embodiment the compound is not acompound of any one of formulae 106-107, 235-243, and 281-285; in oneembodiment the compound is not a compound of any one of formulae 106-107and 242-243; in one embodiment the compound is not a compound of any oneof formulae 74-76, 199-203, 204-210, 281-285, and 286-292; in oneembodiment the compound is not a compound of any one of formulae 14,41-44, 63-65, 74-76, 79-80, 99-100, 106-107, 113-126, 204-210, 133-155,165-173, 177-192, 196-210, 214-243, 249-250, 272-274, 269-271, 275-280,286-292, and 293-296; in one embodiment the compound is not a compoundof any one of formulae 43-47, 56-58, 229, 74-79, 95-97, 99-100, 106-107,113-114, 124-126, 133-138, 154-155, 158-159, 165-167, 199-210, 214-224,226-233, 235-243, 249-250, and 279-292; in one embodiment the compoundis not a compound of any one of formulae 503, 526-528, 531, 542, 551,554, 557, 559, 565, 569, 572-574, 577, 585, 587, 598-600, 602, 603, 605,607, 608, and 609; in one embodiment the compound is not a compound ofany one of formulae 525-527, 533, 534, 542, 554, 557, 559, 563, 565-567,569, 572-579, 585, 587-589, 591-595, 597-600, 602, 604-605, and 607-611;in one embodiment the compound is not a compound of any one of formulae598-600, 577, and 608; in one embodiment the compound is not a compoundof formula 557 or 585; in one embodiment the compound is not a compoundof any one of formulae 557, 577, 585, 602, 607, and 609; in oneembodiment the compound is not a compound of formula 544; in oneembodiment the compound is not a compound of any one of formulae 528,531, 551, and 605; in one embodiment the compound is not a compound ofany one of formulae 559, 598-600 and 608; and in one embodiment thecompound is not a compound of formula 585.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. All though only one delocalized resonance structure maybe depicted, all such forms are contemplated within the scope of theiinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

The compositions of this invention optionally comprise salts of thecompounds herein, especially pharmaceutically acceptable non-toxic saltscontaining, for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺². Such salts mayinclude those derived by combination of appropriate cations such asalkali and alkaline earth metal ions or ammonium and quaternary aminoions with an acid anion moiety, typically a carboxylic acid. Monovalentsalts are preferred if a water soluble salt is desired.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the amino acidsdescribed above are suitable, especially the naturally-occurring aminoacids found as protein components, although the amino acid typically isone bearing a side chain with a basic or acidic group, e.g., lysine,arginine or glutamic acid, or a neutral group such as glycine, serine,threonine, alanine, isoleucine, or leucine.

Methods of Inhibition of Inflammation

Another aspect of the invention relates to methods of inhibitinginflammation comprising the step of treating a sample or subjectsuspected of needing such inhibition with a composition of theinvention.

Compositions of the invention may act as inhibitors of inflammation oras intermediates for such inhibitors or have other utilities asdescribed below. The inhibitors may bind to locations on the surface orin a cavity of a cell having a geometry unique to the specific compoundor a portion of the compound. Compositions binding a cell may bind withvarying degrees of reversibility. Those compounds binding substantiallyirreversibly are ideal candidates for use in this method of theinvention. Once labeled, the substantially irreversibly bindingcompositions are useful as probes for the detection of inflammation.Accordingly, the invention relates to methods of detecting inflammationin a sample or subject suspected of being inflamed or of including aninflammatory agent, comprising the steps of: treating such a sample orsubject with a composition comprising a compound of the invention boundto (or comprising) a label; and observing the effect of the sample onthe activity of the label. Suitable labels are well known in thediagnostics field and include stable free radicals, fluorophores,radioisotopes, enzymes, chemiluminescent groups and chromogens. Thecompounds herein are labeled in conventional fashion using functionalgroups such as hydroxyl or amino.

Within the context of the invention a “sample” suspected of beinginflammed or including an inflammatory agent include natural or man-madematerials such as living organisms; tissue or cell cultures; biologicalsamples such as biological material samples (blood, serum, urine,cerebrospinal fluid, tears, sputum, saliva, tissue samples, and thelike); laboratory samples; food, water, or air samples; bioproductsamples such as extracts of cells, particularly recombinant cellssynthesizing a desired glycoprotein; and the like. Samples can becontained in any medium including water and organic solvent\watermixtures. Samples include living organisms such as humans, and man madematerials such as cell cultures.

The treating step of the invention comprises adding the compound of theinvention to the sample or it comprises adding a precursor of thecompound to the sample. The addition step comprises any method ofadministration as described herein.

If desired, the anti-inflammatory activity of a compound of theinvention after application of the composition can be observed by anymethod including direct and indirect methods of detecting such activity.Quantitative, qualitative, and semiquantitative methods of determiningsuch activity are all contemplated. Typically one of the screeningmethods described above are applied, however, any other method such asobservation of the physiological properties of a living organism arealso applicable.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(S) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(S) in an amount of, for example,0.075 to 20% w/w (including active ingredient(S) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(S) with or without stabilizer(S) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of inflammation as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provided compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against existing inflammation,the method of delivery, and the pharmaceutical formulation, and will bedetermined by the clinician using conventional dose escalation studies.It can be expected to be from about 0.0001 to about 100 mg/kg bodyweight per day. Typically, from about 0.01 to about 10 mg/kg body weightper day. More typically, from about 0.01 to about 5 mg/kg body weightper day. More typically, from about 0.05 to about 0.5 mg/kg body weightper day. For example, the daily candidate dose for an adult human ofapproximately 70 kg body weight will range from 1 mg to 1000 mg,preferably between 5 mg and 500 mg, and may take the form of single ormultiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

Active ingredients of the invention can also be used in combination withother active ingredients. Such combinations are typically selected basedon the condition to be treated, cross-reactivities of ingredients andpharmaco-properties of the combination. For example, when treatinginflammation the compositions of the invention can be combined withother anti-inflammatory compounds.

It is also possible to combine any compound of the invention with one ormore other active ingredients in a unitary dosage form for simultaneousor sequential administration to a patient. The combination therapy maybe administered as a simultaneous or sequential regimen. Whenadministered sequentially, the combination may be administered in two ormore administrations.

The combination therapy may provide “synergy” or a “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together. A synergisticanti-inflammatory effect denotes an anti-inflammatory effect which isgreater than the predicted purely additive effects of the individualcompounds of the combination.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possessnoanti-inflammatory activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The phosphonate prodrugs of theinvention typically will be stable in the digestive system but aresubstantially hydrolyzed to the parental drug in the digestive lumen,liver or other metabolic organ, or within cells in general.

Exemplary Methods of Making the Compounds of the Invention.

The invention also relates to methods of making the compounds of theinvention. The compounds are prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. However, many of the known techniques are elaborated inCompendium of Organic Synthetic Methods (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., AdvancedOrganic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985),Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief(Pergamon Press, New York, 1993 printing).

Schemes and Examples

General aspects of these exemplary methods are described below and inthe Examples. Each of the products of the following processes isoptionally separated, isolated, and/or purified prior to its use insubsequent processes.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used inconnection with a chemical synthetic operation, mean contacting, mixing,reacting, allowing to react, bringing into contact, and other termscommon in the art for indicating that one or more chemical entities istreated in such a manner as to convert it to one or more other chemicalentities. This means that “treating compound one with compound two” issynonymous with “allowing compound one to react with compound two”,“contacting compound one with compound two”, “reacting compound one withcompound two”, and other expressions common in the art of organicsynthesis for reasonably indicating that compound one was “treated”,“reacted”, “allowed to react”, etc., with compound two. For example,treating indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically −78°C. to 150° C., more typically −78° C. to 100° C., still more typically0° C. to 100° C.), reaction vessels (typically glass, plastic, metal),solvents, pressures, atmospheres (typically air for oxygen and waterinsensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis are used inselecting the conditions and apparatus for “treating” in a givenprocess. In particular, one of ordinary skill in the art of organicsynthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

Modifications of each of the exemplary schemes and in the examples(hereafter “exemplary schemes”) leads to various analogs of the specificexemplary materials produce. The above-cited citations describingsuitable methods of organic synthesis are applicable to suchmodifications.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3)283-302). Racemic mixtures of chiral compounds of the invention can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched xanthene. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

Anti-Inflammatory Activity

Compositions of the invention are screened for anti-inflammatoryactivity by any of the conventional techniques for evaluating enzymeactivity. Within the context of the invention, typically compositionsare first screened for inhibitory activity in vitro and compositionsshowing inhibitory activity are then screened for activity in vivo.Compositions having in vitro Ki (inhibitory constants) of less thenabout 5×10⁻⁶ M, typically less than about 1×10⁻⁷ M and preferably lessthan about 5×10⁻⁸ M are preferred for in vivo use. For example, theanti-inflammatory properties of the compounds of the invetion can beassessed using assays available to the art worker, e.g., using themethods described in Brit. J. Pharmacol., 1997, 121, 171; Anal.Biochem., 1995, 231, 354; Pharmacol. Exp. Ther., 1992, 263, 1195; and/orEur. J. Pharmacol., 1995, 281, 107.

The anti-inflammatory properties of a compound may also be assessed bymeasuring the inhibition of IMPDH, e.g., using the following generalmethod.

IMPDH Inhibition Assay Protocol

The following reagents are used to measure the IMPDH inhibitoryactivity: Tris-HCL pH=8.0 (Sigma #41K8411); KCl (Sigma # P-9541); EDTA(Sigma # E-7889); DTT (Sigma # D-9779); β-NAD+ (Sigma#N-6522); IMP(Sigma #I-4625); IMPDH II (Sigma #I-1782); Glycerol (Sigma# G-7757); anda 96 Well UV Transparent (BD Falcon #).

The following solutions are prepared, with all components diluted inde-ionized water: Solution #1 is 135 mM Tris, pH=8.0; Solution #2 is 625mM KCl, 19 uM EDTA, 6.5 mM DTT, pH=8.0; Solution #3 is 13 mM β-NAD+;Solution #4 is 6 mM IMP; Solution #5 is 20 mM Tris, 0.5 mM EDTA, 1 mMDTT, 10% Glycerol.

To prepare the reagent cocktail, combine 11.5 mL of Solution #1, 2.5 mLof Solution #2, and 0.5 mL of Solution #3, and adjust the to pH=8.0.Dilute IMPDH II in Solution #5 to a final concentration of 11.5 nM.

To determine the IMPDH inhibition, first add 280 μL of the reagentcocktail and 10 uL of Solution #4 to each Reaction. Then, initiate thereaction by the addition of 10 μL of IMPDH II enzyme and read the plateat time=0 min at 340 nm. Then, incubate the plate at 37° C. for 5 hours.Finally, read the plate at 340 nM after 5 hrs.

The final assay concentrations, at 37° C., are: Tris, 100 mM, pH 8.0;potassium chloride, 100 mM; EDTA, 3.1 mM; DTT, 1.1 mM; glycerol, 0.33%(v/v); Beta-NAD, 0.42 mM; and IMP, 0.2 mM.

The anti-inflammatory properties of the compounds can also be assessedby measuring the inhibition of cell proliferation, e.g., using thefollowing method.

Cell Proliferation Assay Protocol

Peripheral blood mononuclear cells (1×10⁵ cells/well) are cultured inmicrotiter plates with RPMI-1640 (Gibco) supplemented with 5% fetal calfserum, penicillin and streptomycin, with a final volume of 0.2 mL.Phytohemagglutinin (PHA-L) is used at a concentration of 10 μg/mL tostimulate cell proliferation. The cells are incubated at 37° C. in anatmosphere of air with 7% CO₂ and 100% humidity for 72 hrs. A pulse of0.5 μCi/well tritiated thymidine is added for the final 6-16 h culture.Cells are harvested and the uptake of radioactivity measured by standardscintillation procedures.

Examples General Section

A number of exemplary methods for the preparation of compounds of theinvention are provided herein, for example, in the Examples hereinbelow.These methods are intended to illustrate the nature of such preparationsare not intended to limit the scope of applicable methods. Certaincompounds of the invention can be used as intermediates for thepreparation of other compounds of the invention. For example, theinterconversion of various phosphonate compounds of the invention isillustrated below.

Interconversions of the Phosphonates R-LINK-P(O)(^(OR) ¹)₂,R-LINK-P(O)(^(OR) ¹)(OH) AND R-LINK-P(O)(OH)₂.

The following schemes 32-38 described the preparation of phosphonateesters of the general structure R-link-P(O)(^(OR) ¹)₂, in which thegroups R¹ may be the same or different. The R¹ groups attached to aphosphonate ester, or to precursors thereto, may be changed usingestablished chemical transformations. The interconversion reactions ofphosphonates are illustrated in Scheme S32. The group R in Scheme 32represents the substructure, i.e. the drug “scaffold, to which thesubstituent link-P(O)(^(OR) ¹)₂ is attached, either in the compounds ofthe invention, or in precursors thereto. At the point in the syntheticroute of conducting a phosphonate interconversion, certain functionalgroups in R may be protected. The methods employed for a givenphosphonate transformation depend on the nature of the substituent R¹,and of the substrate to which the phosphonate group is attached. Thepreparation and hydrolysis of phosphonate esters is described in OrganicPhosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.9ff.

In general, synthesis of phosphonate esters is achieved by coupling anucleophile amine or alcohol with the corresponding activatedphosphonate electrophilic precursor. For example, chlorophosphonateaddition on to 5′-hydroxy of nucleoside is a well known method forpreparation of nucleoside phosphate monoesters. The activated precursorcan be prepared by several well known methods. Chlorophosphonates usefulfor synthesis of the prodrugs are prepared from thesubstituted-1,3-propanediol (Wissner, et al, (1992) J. Med. Chem.35:1650). Chlorophosphonates are made by oxidation of the correspondingchlorophospholanes (Anderson, et al, (1984) J. Org. Chem. 49:1304) whichare obtained by reaction of the substituted diol with phosphorustrichloride. Alternatively, the chlorophosphonate agent is made bytreating substituted-1,3-diols with phosphorusoxychloride (Patois, etal, (1990) J. Chem. Soc. Perkin Trans. 1,1577). Chlorophosphonatespecies may also be generated in situ from corresponding cyclicphosphites (Silverburg, et al., (1996) Tetrahedron lett., 37:771-774),which in turn can be either made from chlorophospholane orphosphoramidate intermediate. Phosphoroflouridate intermediate preparedeither from pyrophosphate or phosphoric acid may also act as precursorin preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedronlett., 29:5763-66).

Phosphonate prodrugs of the present invention may also be prepared fromthe free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1;Campbell, (1992) J. Org. Chem. 57:6331), and other acid couplingreagents including, but not limited to, carbodiimides (Alexander, et al,(1994) Collect. Czech. Chem. Commun. 59:1853; Casara et al, (1992)Bioorg. Med. Chem. Lett. 2:145; Ohashi et al, (1988) Tetrahedron Lett.,29:1189), and benzotriazolyloxytris-(dimethylamino)phosphonium salts(Campagne et al (1993) Tetrahedron Lett. 34:6743).

Aryl halides undergo Ni⁺² catalyzed reaction with phosphite derivativesto give aryl phosphonate containing compounds (Balthazar, et al (1980)J. Org. Chem. 45:5425). Phosphonates may also be prepared from thechlorophosphonate in the presence of a palladium catalyst using aromatictriflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:2831; Lu et al(1987) Synthesis 726). In another method, aryl phosphonate esters areprepared from aryl phosphates under anionic rearrangement conditions(Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991)Synthesis, 691). N-Alkoxy aryl salts with alkali metal derivatives ofcyclic alkyl phosphonate provide general synthesis forheteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114).These above mentioned methods can also be extended to compounds wherethe W⁵ group is a heterocycle. Cyclic-1,3-propanyl prodrugs ofphosphonates are also synthesized from phosphonic diacids andsubstituted propane-1,3-diols using a coupling reagent such as1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g.,pyridine). Other carbodiimide based coupling agents like1,3-disopropylcarbodiimide or water soluble reagent,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) canalso be utilized for the synthesis of cyclic phosphonate prodrugs.

The conversion of a phosphonate diester S32.1 into the correspondingphosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by anumber of methods. For example, the ester S32.1 in which R¹ is anaralkyl group such as benzyl, is converted into the monoester compoundS32.2 by reaction with a tertiary organic base such asdiazabicyclooctane (DABCO) or quinuclidine, as described in J. Org.Chem. (1995) 60:2946. The reaction is performed in an inert hydrocarbonsolvent such as toluene or xylene, at about 110° C. The conversion ofthe diester S32.1 in which R¹ is an aryl group such as phenyl, or analkenyl group such as allyl, into the monoester S32.2 is effected bytreatment of the ester S32.1 with a base such as aqueous sodiumhydroxide in acetonitrile or lithium hydroxide in aqueoustetrahydrofuran. Phosphonate diesters S32.1 in which one of the groupsR¹ is aralkyl, such as benzyl, and the other is alkyl, is converted intothe monoesters S32.2 in which R¹ is alkyl by hydrogenation, for exampleusing a palladium on carbon catalyst. Phosphonate diesters in which bothof the groups R¹ are alkenyl, such as allyl, is converted into themonoester S32.2 in which R¹ is alkenyl, by treatment withchlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueousethanol at reflux, optionally in the presence of diazabicyclooctane, forexample by using the procedure described in J. Org. Chem. (1973)38:3224, for the cleavage of allyl carboxylates.

The conversion of a phosphonate diester S32.1 or a phosphonate monoesterS32.2 into the corresponding phosphonic acid S32.3 (Scheme 32, Reactions2 and 3) can be effected by reaction of the diester or the monoesterwith trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm.,(1979) 739. The reaction is conducted in an inert solvent such as, forexample, dichloromethane, optionally in the presence of a silylatingagent such as bis(trimethylsilyl)trifluoroacetamide, at ambienttemperature. A phosphonate monoester S32.2 in which R¹ is aralkyl suchas benzyl, is converted into the corresponding phosphonic acid S32.3 byhydrogenation over a palladium catalyst, or by treatment with hydrogenchloride in an ethereal solvent such as dioxane. A phosphonate monoesterS32.2 in which R¹ is alkenyl such as, for example, allyl, is convertedinto the phosphonic acid S32.3 by reaction with Wilkinson's catalyst inan aqueous organic solvent, for example in 15% aqueous acetonitrile, orin aqueous ethanol, for example using the procedure described in Helv.Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis ofphosphonate esters S32.1 in which R¹ is benzyl is described in J. Org.Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonateesters S32.1 in which R¹ is phenyl is described in J. Am. Chem. Soc.(1956) 78:2336.

The conversion of a phosphonate monoester S32.2 into a phosphonatediester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R¹group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl iseffected by a number of reactions in which the substrate S32.2 isreacted with a hydroxy compound R¹OH, in the presence of a couplingagent. Typically, the second phosphonate ester group is different thanthe first introduced phosphonate ester group, i.e. R¹ is followed by theintroduction of R² where each of R¹ and R² is alkyl, aralkyl, haloalkylsuch as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2is converted to S32.1a. Suitable coupling agents are those employed forthe preparation of carboxylate esters, and include a carbodiimide suchas dicyclohexylcarbodiimide, in which case the reaction is preferablyconducted in a basic organic solvent such as pyridine, or(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PYBOP, Sigma), in which case the reaction is performed in a polarsolvent such as dimethylformamide, in the presence of a tertiary organicbase such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in whichcase the reaction is conducted in a basic solvent such as pyridine, inthe presence of a triaryl phosphine such as triphenylphosphine.Alternatively, the conversion of the phosphonate monoester S32.2 to thediester S32.1 is effected by the use of the Mitsunobu reaction, asdescribed above (Scheme 7). The substrate is reacted with the hydroxycompound R¹OH, in the presence of diethyl azodicarboxylate and atriarylphosphine such as triphenyl phosphine. Alternatively, thephosphonate monoester S32.2 is transformed into the phosphonate diesterS32.1, in which the introduced R¹ group is alkenyl or aralkyl, byreaction of the monoester with the halide R¹Br, in which R¹ is asalkenyl or aralkyl. The alkylation reaction is conducted in a polarorganic solvent such as dimethylformamide or acetonitrile, in thepresence of a base such as cesium carbonate. Alternatively, thephosphonate monoester is transformed into the phosphonate diester in atwo step procedure. In the first step, the phosphonate monoester S32.2is transformed into the chloro analog RP(O)(^(OR) ¹)Cl by reaction withthionyl chloride or oxalyl chloride and the like, as described inOrganic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley,1976, p. 17, and the thus-obtained product RP(O)(^(OR) ¹)Cl is thenreacted with the hydroxy compound R¹OH, in the presence of a base suchas triethylamine, to afford the phosphonate diester S32.1.

A phosphonic acid R-link-P(O)(OH)₂ is transformed into a phosphonatemonoester RP(O)(^(OR) ¹)(OH) (Scheme 32, Reaction 5) by means of themethods described above of for the preparation of the phosphonatediester R-link-P(O)(OR¹)₂ S32.1, except that only one molar proportionof the component R¹OH or R¹Br is employed. Dialkyl phosphonates may beprepared according to the methods of: Quast et al (1974) Synthesis 490;Stowell et al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.

A phosphonic acid R-link-P(O)(OH)₂ S32.3 is transformed into aphosphonate diester R-link-P(O)(^(OR) ¹)₂ S32.1 (Scheme 32, Reaction 6)by a coupling reaction with the hydroxy compound R¹OH, in the presenceof a coupling agent such as Aldrithiol-2 (Aldrich) andtriphenylphosphine. The reaction is conducted in a basic solvent such aspyridine. Alternatively, phosphonic acids S32.3 are transformed intophosphonic esters S32.1 in which R¹ is aryl, by means of a couplingreaction employing, for example, dicyclohexylcarbodiimide in pyridine atca 70° C. Alternatively, phosphonic acids S32.3 are transformed intophosphonic esters S32.1 in which R¹ is alkenyl, by means of analkylation reaction. The phosphonic acid is reacted with the alkenylbromide R¹Br in a polar organic solvent such as acetonitrile solution atreflux temperature, the presence of a base such as cesium carbonate, toafford the phosphonic ester S32.1.

Preparation of Phosphonate Carbamates.

Phosphonate esters may contain a carbamate linkage. The preparation ofcarbamates is described in Comprehensive Organic Functional GroupTransformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff,and in Organic Functional Group Preparations, by S. R. Sandler and W.Karo, Academic Press, 1986, p. 260ff. The carbamoyl group may be formedby reaction of a hydroxy group according to the methods known in theart, including the teachings of Ellis, U.S. 2002/0103378 A1 and Hajima,U.S. Pat. No. 6,018,049.

Scheme 33 illustrates various methods by which the carbamate linkage issynthesized. As shown in Scheme 33, in the general reaction generatingcarbamates, an alcohol S33.1, is converted into the activated derivativeS33.2 in which Lv is a leaving group such as halo, imidazolyl,benztriazolyl and the like, as described herein. The activatedderivative S33.2 is then reacted with an amine S33.3, to afford thecarbamate product S33.4. Examples 1-7 in Scheme 33 depict methods bywhich the general reaction is effected. Examples 8-10 illustratealternative methods for the preparation of carbamates.

Scheme 33, Example 1 illustrates the preparation of carbamates employinga chloroformyl derivative of the alcohol S33.5. In this procedure, thealcohol S33.5 is reacted with phosgene, in an inert solvent such astoluene, at about 0° C., as described in Org. Syn. Coll. Vol. 3, 167,1965, or with an equivalent reagent such as trichloromethoxychloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, toafford the chloroformate S33.6. The latter compound is then reacted withthe amine component S33.3, in the presence of an organic or inorganicbase, to afford the carbamate S33.7. For example, the chloroformylcompound S33.6 is reacted with the amine S33.3 in a water-misciblesolvent such as tetrahydrofuran, in the presence of aqueous sodiumhydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yieldthe carbamate S33.7. Alternatively, the reaction is performed indichloromethane in the presence of an organic base such asdiisopropylethylamine or dimethylaminopyridine.

Scheme 33, Example 2 depicts the reaction of the chloroformate compoundS33.6 with imidazole to produce the imidazolide S33.8. The imidazolideproduct is then reacted with the amine S33.3 to yield the carbamateS33.7. The preparation of the imidazolide is performed in an aproticsolvent such as dichloromethane at 0°, and the preparation of thecarbamate is conducted in a similar solvent at ambient temperature,optionally in the presence of a base such as dimethylaminopyridine, asdescribed in J. Med. Chem., 1989, 32, 357.

Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6with an activated hydroxyl compound R″OH, to yield the mixed carbonateester S33.10. The reaction is conducted in an inert organic solvent suchas ether or dichloromethane, in the presence of a base such asdicyclohexylamine or triethylamine. The hydroxyl component R″OH isselected from the group of compounds S33.19-S33.24 shown in Scheme 33,and similar compounds. For example, if the component R″OH ishydroxybenztriazole S33.19, N-hydroxysuccinimide S33.20, orpentachlorophenol, S33.21, the mixed carbonate S33.10 is obtained by thereaction of the chloroformate with the hydroxyl compound in an etherealsolvent in the presence of dicyclohexylamine, as described in Can. J.Chem., 1982, 60, 976. A similar reaction in which the component R″OH ispentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed in anethereal solvent in the presence of triethylamine, as described in Syn.,1986, 303, and Chem. Ber. 118, 468, 1985.

Scheme 33 Example 4 illustrates the preparation of carbamates in whichan alkyloxycarbonylimidazole S33.8 is employed. In this procedure, analcohol S33.5 is reacted with an equimolar amount of carbonyldiimidazole S33.11 to prepare the intermediate S33.8. The reaction isconducted in an aprotic organic solvent such as dichloromethane ortetrahydrofuran. The acyloxyimidazole S33.8 is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is performed in an aprotic organic solvent such asdichloromethane, as described in Tet. Lett., 42, 2001, 5227, to affordthe carbamate S33.7.

Scheme 33, Example 5 illustrates the preparation of carbamates by meansof an intermediate alkoxycarbonylbenztriazole S33.13. In this procedure,an alcohol ROH is reacted at ambient temperature with an equimolaramount of benztriazole carbonyl chloride S33.12, to afford thealkoxycarbonyl product S33.13. The reaction is performed in an organicsolvent such as benzene or toluene, in the presence of a tertiaryorganic amine such as triethylamine, as described in Synthesis., 1977,704. The product is then reacted with the amine R′NH₂ to afford thecarbamate S33.7. The reaction is conducted in toluene or ethanol, atfrom ambient temperature to about 80° C. as described in Synthesis.,1977, 704.

Scheme 33, Example 6 illustrates the preparation of carbamates in whicha carbonate (R″O)₂CO, S33.14, is reacted with an alcohol S33.5 to affordthe intermediate alkyloxycarbonyl intermediate S33.15. The latterreagent is then reacted with the amine R′NH₂ to afford the carbamateS33.7. The procedure in which the reagent S33.15 is derived fromhydroxybenztriazole S33.19 is described in Synthesis, 1993, 908; theprocedure in which the reagent S33.15 is derived fromN-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992, 2781; theprocedure in which the reagent S33.15 is derived from 2-hydroxypyridineS33.23 is described in Tet. Lett., 1991, 4251; the procedure in whichthe reagent S33.15 is derived from 4-nitrophenol S33.24 is described inSynthesis. 1993, 103. The reaction between equimolar amounts of thealcohol ROH and the carbonate S33.14 is conducted in an inert organicsolvent at ambient temperature.

Scheme 33, Example 7 illustrates the preparation of carbamates fromalkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformateS33.6 is reacted with an azide, for example sodium azide, to afford thealkoxycarbonyl azide S33.16. The latter compound is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is conducted at ambient temperature in a polar aprotic solventsuch as dimethylsulfoxide, for example as described in Synthesis., 1982,404.

Scheme 33, Example 8 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and the chloroformyl derivativeof an amine S33.17. In this procedure, which is described in SyntheticOrganic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, thereactants are combined at ambient temperature in an aprotic solvent suchas acetonitrile, in the presence of a base such as triethylamine, toafford the carbamate S33.7.

Scheme 33, Example 9 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an isocyanate S33.18. In thisprocedure, which is described in Synthetic Organic Chemistry, R. B.Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined atambient temperature in an aprotic solvent such as ether ordichloromethane and the like, to afford the carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an amine R′NH₂. In thisprocedure, which is described in Chem. Lett. 1972, 373, the reactantsare combined at ambient temperature in an aprotic organic solvent suchas tetrahydrofuran, in the presence of a tertiary base such astriethylamine, and selenium. Carbon monoxide is passed through thesolution and the reaction proceeds to afford the carbamate S33.7.

Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,Monoamidates, Diesters and Monoesters.

A number of methods are available for the conversion of phosphonic acidsinto amidates and esters. In one group of methods, the phosphonic acidis either converted into an isolated activated intermediate such as aphosphoryl chloride, or the phosphonic acid is activated in situ forreaction with an amine or a hydroxy compound.

The conversion of phosphonic acids into phosphoryl chlorides isaccomplished by reaction with thionyl chloride, for example as describedin J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063,or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride,as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem.,1994, 59, 6144, or by reaction with phosphorus pentachloride, asdescribed in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995,38, 1372. The resultant phosphoryl chlorides are then reacted withamines or hydroxy compounds in the presence of a base to afford theamidate or ester products.

Phosphonic acids are converted into activated imidazolyl derivatives byreaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem.Comm. (1991) 312, or Nucleosides & Nucleotides (2000) 19:1885. Activatedsulfonyloxy derivatives are obtained by the reaction of phosphonic acidswith trichloromethylsulfonyl chloride or withtriisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996)7857, or Bioorg. Med. Chem. Lett. (1998) 8:663. The activatedsulfonyloxy derivatives are then reacted with amines or hydroxycompounds to afford amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant arecombined in the presence of a diimide coupling agent. The preparation ofphosphonic amidates and esters by means of coupling reactions in thepresence of dicyclohexyl carbodiimide is described, for example, in J.Chem. Soc., Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987)52:2792. The use of ethyl dimethylaminopropyl carbodiimide foractivation and coupling of phosphonic acids is described in Tet. Lett.,(2001) 42:8841, or Nucleosides & Nucleotides (2000) 19:1885.

A number of additional coupling reagents have been described for thepreparation of amidates and esters from phosphonic acids. The agentsinclude Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem.,1995, 60, 5214, and J. Med. Chem. (1997) 40:3842,mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J.Med. Chem. (1996) 39:4958, diphenylphosphoryl azide, as described in J.Org. Chem. (1984) 49:1158,1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) asdescribed in Bioorg. Med. Chem. Lett. (1998) 8:1013,bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), asdescribed in Tet. Lett., (1996) 37:3997,2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described inNucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, asdescribed in J. Med. Chem., 1988, 31, 1305.

Phosphonic acids are converted into amidates and esters by means of theMitsunobu reaction, in which the phosphonic acid and the amine orhydroxy reactant are combined in the presence of a triaryl phosphine anda dialkyl azodicarboxylate. The procedure is described in Org. Lett.,2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.

Phosphonic esters are also obtained by the reaction between phosphonicacids and halo compounds, in the presence of a suitable base. The methodis described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem.Soc. Perkin Trans., 1,1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372,or Tet. Lett., 2002, 43, 1161.

Schemes 34-37 illustrate the conversion of phosphonate esters andphosphonic acids into carboalkoxy-substituted phosphonbisamidates(Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters(Scheme 36) and phosphonate diesters, (Scheme 37). Scheme 38 illustratessynthesis of gem-dialkyl amino phosphonate reagents.

Scheme 34 illustrates various methods for the conversion of phosphonatediesters S34.1 into phosphonbisamidates S34.5. The diester S34.1,prepared as described previously, is hydrolyzed, either to the monoesterS34.2 or to the phosphonic acid S34.6. The methods employed for thesetransformations are described above. The monoester S34.2 is convertedinto the monoamidate S34.3 by reaction with an aminoester S34.9, inwhich the group R² is H or alkyl; the group R^(4b) is a divalentalkylene moiety such as, for example, CHCH₃, CHCH₂CH₃, CH(CH(CH₃)₂),CH(CH₂Ph), and the like, or a side chain group present in natural ormodified aminoacids; and the group R^(5b) is C₁-C₁₂ alkyl, such asmethyl, ethyl, propyl, isopropyl, or isobutyl; C₆-C₂₀ aryl, such asphenyl or substituted phenyl; or C₆-C₂₀ arylalkyl, such as benzyl orbenzyhydryl. The reactants are combined in the presence of a couplingagent such as a carbodiimide, for example dicyclohexyl carbodiimide, asdescribed in J. Am. Chem. Soc., (1957) 79:3575, optionally in thepresence of an activating agent such as hydroxybenztriazole, to yieldthe amidate product S34.3. The amidate-forming reaction is also effectedin the presence of coupling agents such as BOP, as described in J. Org.Chem. (1995) 60:5214, Aldrithiol, PYBOP and similar coupling agents usedfor the preparation of amides and esters. Alternatively, the reactantsS34.2 and S34.9 are transformed into the monoamidate S34.3 by means of aMitsunobu reaction. The preparation of amidates by means of theMitsunobu reaction is described in J. Med. Chem. (1995) 38:2742.Equimolar amounts of the reactants are combined in an inert solvent suchas tetrahydrofuran in the presence of a triaryl phosphine and a dialkylazodicarboxylate. The thus-obtained monoamidate ester S34.3 is thentransformed into amidate phosphonic acid S34.4. The conditions used forthe hydrolysis reaction depend on the nature of the R¹ group, asdescribed previously. The phosphonic acid amidate S34.4 is then reactedwith an aminoester S34.9, as described above, to yield the bisamidateproduct S34.5, in which the amino substituents are the same ordifferent. Alternatively, the phosphonic acid S34.6 may be treated withtwo different amino ester reagents simulataneously, i.e. S34.9 where R²,R^(4b) or R^(5b) are different. The resulting mixture of bisamidateproducts S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 1. In thisprocedure, a dibenzyl phosphonate S34.14 is reacted withdiazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org.Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate S34.15. Theproduct is then reacted with equimolar amounts of ethyl alaninate S34.16and dicyclohexyl carbodiimide in pyridine, to yield the amidate productS34.17. The benzyl group is then removed, for example by hydrogenolysisover a palladium catalyst, to give the monoacid product S34.18 which maybe unstable according to J. Med. Chem. (1997) 40(23):3842. This compoundS34.18 is then reacted in a Mitsunobu reaction with ethyl leucinateS34.19, triphenyl phosphine and diethylazodicarboxylate, as described inJ. Med. Chem., 1995, 38, 2742, to produce the bisamidate product S34.20.

Using the above procedures, but employing in place of ethyl leucinateS34.19 or ethyl alaninate S34.16, different aminoesters S34.9, thecorresponding products S34.5 are obtained.

Alternatively, the phosphonic acid S34.6 is converted into thebisamidate S34.5 by use of the coupling reactions described above. Thereaction is performed in one step, in which case the nitrogen-relatedsubstituents present in the product S34.5 are the same, or in two steps,in which case the nitrogen-related substituents can be different.

An example of the method is shown in Scheme 34, Example 2. In thisprocedure, a phosphonic acid S34.6 is reacted in pyridine solution withexcess ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, forexample as described in J. Chem. Soc., Chem. Comm., 1991, 1063, to givethe bisamidate product S34.22.

Using the above procedures, but employing, in place of ethylphenylalaninate, different aminoesters S34.9, the corresponding productsS34.5 are obtained.

As a further alternative, the phosphonic acid S34.6 is converted intothe mono or bis-activated derivative S34.7, in which Lv is a leavinggroup such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.The conversion of phosphonic acids into chlorides S34.7 (Lv=Cl) iseffected by reaction with thionyl chloride or oxalyl chloride and thelike, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L.Maeir, eds, Wiley, 1976, p. 17. The conversion of phosphonic acids intomonoimidazolides S34.7 (Lv=imidazolyl) is described in J. Med. Chem.,2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.Alternatively, the phosphonic acid is activated by reaction withtriisopropylbenzenesulfonyl chloride, as described in Nucleosides andNucleotides, 2000, 10, 1885. The activated product is then reacted withthe aminoester S34.9, in the presence of a base, to give the bisamidateS34.5. The reaction is performed in one step, in which case the nitrogensubstituents present in the product S34.5 are the same, or in two steps,via the intermediate S34.11, in which case the nitrogen substituents canbe different.

Examples of these methods are shown in Scheme 34, Examples 3 and 5. Inthe procedure illustrated in Scheme 34, Example 3, a phosphonic acidS34.6 is reacted with ten molar equivalents of thionyl chloride, asdescribed in Zh. Obschei Khim., 1958, 28, 1063, to give the dichlorocompound S34.23. The product is then reacted at reflux temperature in apolar aprotic solvent such as acetonitrile, and in the presence of abase such as triethylamine, with butyl serinate S34.24 to afford thebisamidate product S34.25.

Using the above procedures, but employing, in place of butyl serinateS34.24, different aminoesters S34.9, the corresponding products S34.5are obtained.

In the procedure illustrated in Scheme 34, Example 5, the phosphonicacid S34.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991,312, with carbonyl diimidazole to give the imidazolide S34.S32. Theproduct is then reacted in acetonitrile solution at ambient temperature,with one molar equivalent of ethyl alaninate S34.33 to yield themonodisplacement product S34.S34. The latter compound is then reactedwith carbonyl diimidazole to produce the activated intermediate S34.35,and the product is then reacted, under the same conditions, with ethylN-methylalaninate S34.33a to give the bisamidate product S34.36.

Using the above procedures, but employing, in place of ethyl alaninateS34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9,the corresponding products S34.5 are obtained.

The intermediate monoamidate S34.3 is also prepared from the monoesterS34.2 by first converting the monoester into the activated derivativeS34.8 in which Lv is a leaving group such as halo, imidazolyl etc, usingthe procedures described above. The product S34.8 is then reacted withan aminoester S34.9 in the presence of a base such as pyridine, to givean intermediate monoamidate product S34.3. The latter compound is thenconverted, by removal of the R¹ group and coupling of the product withthe aminoester S34.9, as described above, into the bisamidate S34.5.

An example of this procedure, in which the phosphonic acid is activatedby conversion to the chloro derivative S34.26, is shown in Scheme 34,Example 4. In this procedure, the phosphonic monobenzyl ester S34.15 isreacted, in dichloromethane, with thionyl chloride, as described in Tet.Letters., 1994, 35, 4097, to afford the phosphoryl chloride S34.26. Theproduct is then reacted in acetonitrile solution at ambient temperaturewith one molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 toyield the monoamidate product S34.28. The latter compound ishydrogenated in ethylacetate over a 5% palladium on carbon catalyst toproduce the monoacid product S34.29. The product is subjected to aMitsunobu coupling procedure, with equimolar amounts of butyl alaninateS34.30, triphenyl phosphine, diethylazodicarboxylate and triethylaminein tetrahydrofuran, to give the bisamidate product S34.31.

Using the above procedures, but employing, in place of ethyl3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30, differentaminoesters S34.9, the corresponding products S34.5 are obtained.

The activated phosphonic acid derivative S34.7 is also converted intothe bisamidate S34.5 via the diamino compound S34.10. The conversion ofactivated phosphonic acid derivatives such as phosphoryl chlorides intothe corresponding amino analogs S34.10, by reaction with ammonia, isdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir,eds, Wiley, 1976. The bisamino compound S34.10 is then reacted atelevated temperature with a haloester S34.12 (Hal=halogen, i.e. F, Cl,Br, I), in a polar organic solvent such as dimethylformamide, in thepresence of a base such as 4, 4-dimethylaminopyridine (DMAP) orpotassium carbonate, to yield the bisamidate S34.5. Alternatively, S34.6may be treated with two different amino ester reagents simulataneously,i.e. S34.12 where R^(4b) or R^(5b) are different. The resulting mixtureof bisamidate products S34.5 may then be separable, e.g. bychromatography.

An example of this procedure is shown in Scheme 34, Example 6. In thismethod, a dichlorophosphonate S34.23 is reacted with ammonia to affordthe diamide S34.37. The reaction is performed in aqueous, aqueousalcoholic or alcoholic solution, at reflux temperature. The resultingdiamino compound is then reacted with two molar equivalents of ethyl2-bromo-3-methylbutyrate S34.38, in a polar organic solvent such asN-methylpyrrolidinone at ca. 150° C., in the presence of a base such aspotassium carbonate, and optionally in the presence of a catalyticamount of potassium iodide, to afford the bisamidate product S34.39.

Using the above procedures, but employing, in place of ethyl2-bromo-3-methylbutyrate S34.38, different haloesters S34.12 thecorresponding products S34.5 are obtained.

The procedures shown in Scheme 34 are also applicable to the preparationof bisamidates in which the aminoester moiety incorporates differentfunctional groups. Scheme 34, Example 7 illustrates the preparation ofbisamidates derived from tyrosine. In this procedure, themonoimidazolide S34.32 is reacted with propyl tyrosinate S34.40, asdescribed in Example 5, to yield the monoamidate S34.41. The product isreacted with carbonyl diimidazole to give the imidazolide S34.42, andthis material is reacted with a further molar equivalent of propyltyrosinate to produce the bisamidate product S34.43.

Using the above procedures, but employing, in place of propyl tyrosinateS34.40, different aminoesters S34.9, the corresponding products S34.5are obtained. The aminoesters employed in the two stages of the aboveprocedure can be the same or different, so that bisamidates with thesame or different amino substituents are prepared.

Scheme 35 illustrates methods for the preparation of phosphonatemonoamidates.

In one procedure, a phosphonate monoester S34.1 is converted, asdescribed in Scheme 34, into the activated derivative S34.8. Thiscompound is then reacted, as described above, with an aminoester S34.9,in the presence of a base, to afford the monoamidate product S35.1.

The procedure is illustrated in Scheme 35, Example 1. In this method, amonophenyl phosphonate S35.7 is reacted with, for example, thionylchloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to givethe chloro product S35.8. The product is then reacted, as described inScheme 34, with ethyl alaninate S3, to yield the amidate S35.10.

Using the above procedures, but employing, in place of ethyl alaninateS35.9, different aminoesters S34.9, the corresponding products S35.1 areobtained.

Alternatively, the phosphonate monoester S34.1 is coupled, as describedin Scheme 34, with an aminoester S34.9 to produce the amidate S335.1. Ifnecessary, the R¹ substituent is then altered, by initial cleavage toafford the phosphonic acid S35.2. The procedures for this transformationdepend on the nature of the R¹ group, and are described above. Thephosphonic acid is then transformed into the ester amidate productS35.3, by reaction with the hydroxy compound R³OH, in which the group R³is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the samecoupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobureaction etc) described in Scheme 34 for the coupling of amines andphosphonic acids.

Examples of this method are shown in Scheme 35, Examples and 2 and 3. Inthe sequence shown in Example 2, a monobenzyl phosphonate S35.11 istransformed by reaction with ethyl alaninate, using one of the methodsdescribed above, into the monoamidate S35.12. The benzyl group is thenremoved by catalytic hydrogenation in ethylacetate solution over a 5%palladium on carbon catalyst, to afford the phosphonic acid amidateS35.13. The product is then reacted in dichloromethane solution atambient temperature with equimolar amounts of1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol S35.14,for example as described in Tet. Lett., 2001, 42, 8841, to yield theamidate ester S35.15.

In the sequence shown in Scheme 35, Example 3, the monoamidate S35.13 iscoupled, in tetrahydrofuran solution at ambient temperature, withequimolar amounts of dicyclohexyl carbodiimide and4-hydroxy-N-methylpiperidine S35.16, to produce the amidate esterproduct S35.17.

Using the above procedures, but employing, in place of the ethylalaninate product S35.12 different monoacids S35.2, and in place oftrifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16,different hydroxy compounds R³OH, the corresponding products S35.3 areobtained.

Alternatively, the activated phosphonate ester S34.8 is reacted withammonia to yield the amidate S35.4. The product is then reacted, asdescribed in Scheme 34, with a haloester S35.5, in the presence of abase, to produce the amidate product S35.6. If appropriate, the natureof the R¹ group is changed, using the procedures described above, togive the product S35.3. The method is illustrated in Scheme 35, Example4. In this sequence, the monophenyl phosphoryl chloride S35.18 isreacted, as described in Scheme 34, with ammonia, to yield the aminoproduct S35.19. This material is then reacted in N-methylpyrrolidinonesolution at 170° with butyl 2-bromo-3-phenylpropionate S35.20 andpotassium carbonate, to afford the amidate product S35.21.

Using these procedures, but employing, in place of butyl2-bromo-3-phenylpropionate S35.20, different haloesters S35.5, thecorresponding products S35.6 are obtained.

The monoamidate products S35.3 are also prepared from the doublyactivated phosphonate derivatives S34.7. In this procedure, examples ofwhich are described in Synlett., 1998, 1, 73, the intermediate S34.7 isreacted with a limited amount of the aminoester S34.9 to give themono-displacement product S34.11. The latter compound is then reactedwith the hydroxy compound R³OH in a polar organic solvent such asdimethylformamide, in the presence of a base such asdiisopropylethylamine, to yield the monoamidate ester S35.3.

The method is illustrated in Scheme 35, Example 5. In this method, thephosphoryl dichloride S35.22 is reacted in dichloromethane solution withone molar equivalent of ethyl N-methyl tyrosinate S35.23 anddimethylaminopyridine, to generate the monoamidate S35.24. The productis then reacted with phenol S35.25 in dimethylformamide containingpotassium carbonate, to yield the ester amidate product S35.26.

Using these procedures, but employing, in place of ethyl N-methyltyrosinate S35.23 or phenol S35.25, the aminoesters 34.9 and/or thehydroxy compounds R³OH, the corresponding products S35.3 are obtained.

Scheme 36 illustrates methods for the preparation ofcarboalkoxy-substituted phosphonate diesters in which one of the estergroups incorporates a carboalkoxy substituent.

In one procedure, a phosphonate monoester S34.1, prepared as describedabove, is coupled, using one of the methods described above, with ahydroxyester S36.1, in which the groups R^(4b) and R^(5b) are asdescribed in Scheme 34. For example, equimolar amounts of the reactantsare coupled in the presence of a carbodiimide such as dicyclohexylcarbodiimide, as described in Aust. J. Chem., 1963, 609, optionally inthe presence of dimethylaminopyridine, as described in Tet., 1999, 55,12997. The reaction is conducted in an inert solvent at ambienttemperature.

The procedure is illustrated in Scheme 36, Example 1. In this method, amonophenyl phosphonate S36.9 is coupled, in dichloromethane solution inthe presence of dicyclohexyl carbodiimide, with ethyl3-hydroxy-2-methylpropionate S36.10 to yield the phosphonate mixeddiester S36.11.

Using this procedure, but employing, in place of ethyl3-hydroxy-2-methylpropionate S36.10, different hydroxyesters S33.1, thecorresponding products S33.2 are obtained.

The conversion of a phosphonate monoester S34.1 into a mixed diesterS36.2 is also accomplished by means of a Mitsunobu coupling reactionwith the hydroxyester S36.1, as described in Org. Lett., 2001, 643. Inthis method, the reactants 34.1 and S36.1 are combined in a polarsolvent such as tetrahydrofuran, in the presence of a triarylphosphineand a dialkyl azodicarboxylate, to give the mixed diester S36.2. The R¹substituent is varied by cleavage, using the methods describedpreviously, to afford the monoacid product S36.3. The product is thencoupled, for example using methods described above, with the hydroxycompound R³OH, to give the diester product S36.4.

The procedure is illustrated in Scheme 36, Example 2. In this method, amonoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, inthe presence of triphenylphosphine and diethylazodicarboxylate, withethyl lactate S36.13 to give the mixed diester S36.14. The product isreacted with tris(triphenylphosphine) rhodium chloride (Wilkinsoncatalyst) in acetonitrile, as described previously, to remove the allylgroup and produce the monoacid product S36.15. The latter compound isthen coupled, in pyridine solution at ambient temperature, in thepresence of dicyclohexyl carbodiimide, with one molar equivalent of3-hydroxypyridine S36.16 to yield the mixed diester S36.17.

Using the above procedures, but employing, in place of the ethyl lactateS36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or adifferent hydroxy compound R³OH, the corresponding products S36.4 areobtained.

The mixed diesters S36.2 are also obtained from the monoesters S34.1 viathe intermediacy of the activated monoesters S36.5. In this procedure,the monoester S34.1 is converted into the activated compound S36.5 byreaction with, for example, phosphorus pentachloride, as described in J.Org. Chem., 2001, 66, 329, or with thionyl chloride or oxalyl chloride(Lv=Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, asdescribed in Nucleosides and Nucleotides, 2000, 19, 1885, or withcarbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. Theresultant activated monoester is then reacted with the hydroxyesterS36.1, as described above, to yield the mixed diester S36.2.

The procedure is illustrated in Scheme 36, Example 3. In this sequence,a monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at70° C., with ten equivalents of thionyl chloride, so as to produce thephosphoryl chloride S36.19. The product is then reacted with ethyl4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containingtriethylamine, to give the mixed diester S36.21.

Using the above procedures, but employing, in place of ethyl4-carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, thecorresponding products S36.2 are obtained.

The mixed phosphonate diesters are also obtained by an alternative routefor incorporation of the R³O group into intermediates S36.3 in which thehydroxyester moiety is already incorporated. In this procedure, themonoacid intermediate S36.3 is converted into the activated derivativeS36.6 in which Lv is a leaving group such as chloro, imidazole, and thelike, as previously described. The activated intermediate is thenreacted with the hydroxy compound R³OH, in the presence of a base, toyield the mixed diester product S36.4.

The method is illustrated in Scheme 36, Example 4. In this sequence, thephosphonate monoacid S36.22 is reacted with trichloromethanesulfonylchloride in tetrahydrofuran containing collidine, as described in J.Med. Chem., 1995, 38, 4648, to produce the trichloromethanesulfonyloxyproduct S36.23. This compound is reacted with 3-(morpholinomethyl)phenolS36.24 in dichloromethane containing triethylamine, to yield the mixeddiester product S36.25.

Using the above procedures, but employing, in place of with3-(morpholinomethyl)phenol S36.24, different alcohols R³OH, thecorresponding products S36.4 are obtained.

The phosphonate esters S36.4 are also obtained by means of alkylationreactions performed on the monoesters S34.1. The reaction between themonoacid S34.1 and the haloester S36.7 is performed in a polar solventin the presence of a base such as diisopropylethylamine, as described inAnal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med.Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in thepresence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.

The method is illustrated in Scheme 36, Example 5. In this procedure,the monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionateS36.27 and diisopropylethylamine in dimethylformamide at 80° C. toafford the mixed diester product S36.28.

Using the above procedure, but employing, in place of ethyl2-bromo-3-phenylpropionate S36.27, different haloesters S36.7, thecorresponding products S36.4 are obtained.

Scheme 37 illustrates methods for the preparation of phosphonatediesters in which both the ester substituents incorporate carboalkoxygroups.

The compounds are prepared directly or indirectly from the phosphonicacids S34.6. In one alternative, the phosphonic acid is coupled with thehydroxyester S37.2, using the conditions described previously in Schemes34-36, such as coupling reactions using dicyclohexyl carbodiimide orsimilar reagents, or under the conditions of the Mitsunobu reaction, toafford the diester product S37.3 in which the ester substituents areidentical.

This method is illustrated in Scheme 37, Example 1. In this procedure,the phosphonic acid S34.6 is reacted with three molar equivalents ofbutyl lactate S37.5 in the presence of Aldrithiol-2 and triphenylphosphine in pyridine at ca. 70° C., to afford the diester S37.6.

Using the above procedure, but employing, in place of butyl lactateS37.5, different hydroxyesters S37.2, the corresponding products S37.3are obtained.

Alternatively, the diesters S37.3 are obtained by alkylation of thephosphonic acid S34.6 with a haloester S37.1. The alkylation reaction isperformed as described in Scheme 36 for the preparation of the estersS36.4.

This method is illustrated in Scheme 37, Example 2. In this procedure,the phosphonic acid S34.6 is reacted with excess ethyl3-bromo-2-methylpropionate S37.7 and diisopropylethylamine indimethylformamide at ca. 80° C., as described in Anal. Chem., 1987, 59,1056, to produce the diester S37.8.

Using the above procedure, but employing, in place of ethyl3-bromo-2-methylpropionate S37.7, different haloesters S37.1, thecorresponding products S37.3 are obtained.

The diesters S37.3 are also obtained by displacement reactions ofactivated derivatives S34.7 of the phosphonic acid with thehydroxyesters S37.2. The displacement reaction is performed in a polarsolvent in the presence of a suitable base, as described in Scheme 36.The displacement reaction is performed in the presence of an excess ofthe hydroxyester, to afford the diester product S37.3 in which the estersubstituents are identical, or sequentially with limited amounts ofdifferent hydroxyesters, to prepare diesters S37.3 in which the estersubstituents are different.

The methods are illustrated in Scheme 37, Examples 3 and 4. As shown inExample 3, the phosphoryl dichloride S35.22 is reacted with three molarequivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 intetrahydrofuran containing potassium carbonate, to obtain the diesterproduct S37.10.

Using the above procedure, but employing, in place of ethyl3-hydroxy-2-(hydroxymethyl)propionate S37.9, different hydroxyestersS37.2, the corresponding products S37.3 are obtained.

Scheme 37, Example 4 depicts the displacement reaction between equimolaramounts of the phosphoryl dichloride S35.22 and ethyl2-methyl-3-hydroxypropionate S37.11, to yield the monoester productS37.12. The reaction is conducted in acetonitrile at 70° in the presenceof diisopropylethylamine. The product S37.12 is then reacted, under thesame conditions, with one molar equivalent of ethyl lactate S37.13, togive the diester product S37.14.

Using the above procedures, but employing, in place of ethyl2-methyl-3-hydroxypropionate S37.11 and ethyl lactate S37.13, sequentialreactions with different hydroxyesters S37.2, the corresponding productsS37.3 are obtained.

2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be preparedby the route in Scheme 5. Condensation of 2-methyl-2-propanesulfinamidewith acetone give sulfinyl imine S38.11 (J. Org. Chem. 1999, 64, 12).Addition of dimethyl methylphosphonate lithium to S38.11 afford S38.12.Acidic methanolysis of S38.12 provide amine S38.13. Protection of aminewith Cbz group and removal of methyl groups yield phosphonic acidS38.14, which can be converted to desired S38.15 (Scheme 38a) usingmethods reported earlier on. An alternative synthesis of compound S38.14is also shown in Scheme 38b. Commercially available2-amino-2-methyl-1-propanol is converted to aziridines S38.16 accordingto literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8,893). Aziridine opening with phosphite give S38.17 (Tetrahedron Lett.1980, 21, 1623). Reprotection) of S38.17 affords S38.14.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLE 1 Synthesis of Representative Compounds of Formula 1

Theophylline is readily converted to N-7 carboxylyic esters by simplyalkylation. The ester is first saponified to the corresponding acidderivative. The acid derivative is reacted with aminophosphonate, DIC,and HOAt to afford compounds of formula 1.1. The ester is reduced toaldehyde derivative, for example by reductive amination with anaminophosphonate, NaBH₃CN, and HOAc to provide compounds of formula 1.2.The aldehyde can also be reacted with hydroxylamine hydrocchloride,followed by a triflated phosphonate to give compounds of formula 1.3.

EXAMPLE 2 Synthesis of Representative Compounds of Formula 1

Compounds 2.8, 2.9, and 2.10, can be prepared as follows.Theophylline-7-acetic acid (J. Amer. Che. Soc. 1967, 89, 308) is reactedwith aminoethyl phosphonate, DIC, HOAt to afford compound 2.8.Alternatively, the acid is converted to methyl ester by reaction withdiazomethane, followed by the reduction with DIBAL in THF to giveN-7-aldehyde derivate. This aldehyde is reacted with hydroxylaminehydrochloride in the presence of TEA, followed by treating with NaH andtriflated phosphonate to furnish the desired product 2.10. The reductiveamination of the aldehyde with aminoethyl phosphonate, NaBH₃CN, and HOAcgives compound 2.9.

EXAMPLE 3 Synthesis of Representative Compounds of Formula 2

Theophylline (J. Gen. Chem. USSR 1946, 16, 179; Chem. Ber. 1962, 95 403)is protected with adequate protecting group, followed by reaction withn-BuLi, DMF to generat the 6-formaldehyde derivative. This aldehyde isconverted to analog 3.4 by the reductive amination with aminophosphonatefollowed by the removal of N-7 protecting group. Analog 3.5 is preparedfrom the aldehyde in 3 steps. First the aldehyde is reacted withhydroxylamine to give the corresponding oxime, followed by reaction witha triflated phosphonate and deprotection of N-7 protecting group toprovide a compound of formula 3.5.

EXAMPLE 4 Synthesis of Representative Compounds of Formula 2

Theophylline is protected with acid labile group by treating with NaHand (pivaloyloxy)mehtyl chloride to give 4.11 (J. O. C. 1980, 45, 1711).Compound 4.11 is treated with n-BuLi at −78° C. in THF and reacted withDMF to give 4.12. The reductive amination of 4.12 with aminoethylphosphonate, NaBH₃CN, and HOAc, followed by aqueous hydrochloric acidfurnishes the product 4.14. Aldehyde 4.12 can also be reacted withhydroxylamine hydrochloride in the presence base, followed by reactionwith NaH and a triflated phosphonate, and deprotection with aqueous HClto give compound 4.13.

EXAMPLE 5 Synthesis of Representative Compounds of Formula 3

The synthesis of analogs 5.6, 5.7, and 5.8 is illustrated above.1-Methylxanthine is selectly protected with pivaloyoxymethyl groupfollowed by alkylation at N-4, tp provide a key intermediate forpreparing 5.6-5.8. Hydrogenation to convert the benzyl ester to the acidfollowed by reaction with aminophosphonate gives compound 5.6. Reductionof the benzyl ester to the alcohol, followed by reductive amination withaminophosphonate and acid deprotection affords compound 5.7. Analog 5.8is prepared from the aldehyde stepwise with hydroxylamine, triflatedphosphonate, and deprotection of N-7.

EXAMPLE 6 Synthesis of Representative Compounds of Formula 3

Compounds of formulae 6.18, 6.19, and 6.20 can be synthesized asoutlined above. Compound 6.15 is prepared as previously reported (J. O.C. 1980, 45, 1711). N-7 protected 1-N-methylxanthine 6.15 is alkyatedwith benzyl bromoacetate to provide intermediate 6.16. The hydrogenationof 6.16 in the presence of 10% Pd/C gives the corresponding acidderivative. The acid derivative is reacted with aminoethyl phosphonate,DIC, and HOAt, and deprotected with aqueous HCl to furnish 6.18. Benzylester 6.16 can be reduced with DIBAL in THF to the correspondingaldehyde 6.17. Aldehyde 6.17 is reacted with hydroxylamine hydrochloridein the presence of base (e.g. TEA), followed by reaction with NaH andtriflated phosphonate, and deprotection with aqueous HCl to givecompound 6.20. The reductive amination of 6.17 with aminoethylphosphonate, NaBH3CN, and HOAc, followed by deprotection with aqueousHCl furnishes the desired product 6.19.

EXAMPLE 7 Synthesis of Representative Compounds of Formulae 4 and 5

Metamizole 7.1 can be purchased from Sigma (Cat. No. D8890) or preparedas in DE 259577 and DE 254711. The preparation of the phosphonatelinkage to 7.1 through the carboxylic acid derivatives 7.2, 7.3 and 7.4to give compounds of formula 7.6, 7.7, and 7.8 is illustrated above.Compound 7.1 is dissolved in a suitable solvent such as, for example,DCM and is then treated with AlCl₃ and a suitable anhydride, forexample, succinic anhydride as described in Tett. Lett 42 (2001)1467-1469. The acylated products are purified using reverse phase HPLCor flash chromatography on silica gel to give carboxylic acidderivatives 7.2, 7.3 and 7.4. Metamizole derivatives 7.2, 7.3 and 7.4are independently dissolved in a suitable solvent such as, for example,DMF and treated with an amine phosphonic acid ester of the generalformula 7.5 in the presence of a suitable coupling reagant and tertiaryorganic base to afford the amides 7.6, 7.7, and 7.8.

EXAMPLE 8 Synthesis of Representative Compounds of Formulae 4 and 5

For example, 8.2, 8.3, or 8.4 is dissolved in DMF and treated with 3equivalents of (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PYBOP, Sigma) and 6 equivalents ofdiisopropylamine. The activated esters of 8.2, 8.3 and 8.4 are thenindependently treated with 3 equivalents of the hydrochloride salt ofdiethyl 2-aminoethyl-1-phosphonate 8.6 which is prepared as described inJ. Med. Chem 41 4439-4452. The final products are purified by reversephase or flash chromatography on silica gel to give amides 8.7, 8.8 and8.9. Using the above procedure but employing different phosphonatereagants in the place of 8.6 additional compounds of the invention canbe prepared.

EXAMPLE 9 Synthesis of Representative Compounds of Formulae 6 and 7

Rofecoxib derivative 9.1 can be obtained as described in U.S. Pat. No.5,474,995 Example 24. Compound 1.1 is dissolved in a suitable solventsuch as, for example, DCM and is then treated with AlCl₃ and a suitableanhydride, for example, succinic anhydride as described in Tett. Lett 42(2001) 1467-1469. The acylated products are purified using reverse phaseHPLC or flash chromatography on silica gel to give carboxylic acidderivatives 9.2, 9.3 and 9.4. Rofecoxib derivatives 9.2, 9.3 and 9.4 areindependently dissolved in a suitable solvent such as, for example, DMFand is then treated with an amine phosphonic acid ester of the generalformula 9.5 in the presence of a suitable coupling reagant and tertiaryorganic base to afford the amides 9.6, 9.7 and 9.8.

EXAMPLE 10 Synthesis of Representative Compounds of Formula 6 and 7

Compound 10.2, 10.3, or 10.4 dissolved in DMF, is treated with 3equivalents of (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PYBOP, Sigma) and 6 equivalents ofdiisopropylamine. The activated esters of 10.2, 10.3 and 10.4 are thenindependently treated with 3 equivalents of the hydrochloride salt ofdiethyl 2-aminoethyl-1-phosphonate 10.6 which is prepared as describedin J. Med. Chem 41 4439-4452. The final products are purified by reversephase or flash chromatography on silica gel to give amides 10.7, 10.8and 10.9. Using the above procedure but employing different phosphonatereagants in the place of compound 8.6 additional compounds of theinvention can be prepared.

EXAMPLE 11 Synthesis of Representative Compounds of Formulae 8 and 9

Compound 11.1 is dissolved in a suitable solvent such as, for example,DCM and is then treated with AlCl₃ and a suitable anhydride, forexample, succinic anhydride as described in Tett. Lett 42 (2001)1467-1469. The acylated products are purified using reverse phase HPLCor flash chromatography on silica gel to give carboxylic acidderivatives 11.2, 11.3, 11.4 and 11.5. Compounds 11.2, 11.3, 11.4 and11.5 are independently dissolved in a suitable solvent such as, forexample, DMF and is then treated with an amine phosphonic acid ester ofthe general formula 11.6 in the presence of a suitable coupling reagantand tertiary organic base to afford the amides 11.7, 11.8, 11.9, and11.10.

EXAMPLE 12 Synthesis of Representative Compounds of Formulae 8 and 9

Compound 12.2 12.3, 12.4, or 12.5 is dissolved in DMF and treated with 3equivalents of (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PYBOP, Sigma) and 6 equivalents ofdiisopropylamine. The activated esters of compounds 12.2, 12.3, 12.4 and12.5 are then independently treated with 3 equivalents of thehydrochloride salt of diethyl 2-aminoethyl-1-phosphonate 12.7 which isprepared as described in J. Med. Chem 41 4439-4452. The final productsare purified by reverse phase or flash chromatography on silica gel togive amides 12.8, 12.9, 12.10 and 12.11. Using the above procedure butemploying different phosphonate reagants in the place of 12.7 additionalcompounds of the invention can be prepared.

EXAMPLE 13 Synthesis of Representative Compounds of Formula 10

Intermediate 13.1 is available from Sigma or alternatively can beprepared as described in U.S. Pat. No. 3,591,584. Intermediate 13.2 canbe prepared as described in U.S. Pat. No. 3,891,637 example XI or asdescribe in J. Med. Chem. 14 1171-1175 (1971) and coupled to theappropriately substituted aminonictonic acid using the proceduredescribed in J. Med. Chem. 30 678-682 1987.

Piroxicam derivative 13.2 is treated with an amine phosphonic acid esterof the general formula 13.3 in the presence of a suitable couplingreagant and tertiary organic base to afford the amides 13.4, 13.5, and13.6.

EXAMPLE 14 Synthesis of Representative Compounds of Formula 10

Compound 14.1 and 6-aminonictonic acid are dissolved in a suitablesolvent such as xylene and refluxed with active carbon to giveintermediate 14.5. Piroxicam derivative 14.5 is then dissolved inanhydrous DMF and treated with 3 equivalents ofO-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexaflurophosphate (Sigma) and 6 equivalents of diisopropylethylamine.The activated ester of 14.5 is then treated with 3 equivalents of thehydrochloride salt of diethyl 2-aminoethyl-1-phosphonate 14.6 which isprepared as described in J. Med. Chem 41 4439-4452, to form the amide14.7 which is purified by reverse phase or normal phase chromatography.Using the above procedure but employing different phosphonate reagantsin the place of compound 14.6 additional compounds of the invention canbe prepared.

EXAMPLE 15 Synthesis of Representative Compounds of Formula 12

Valdecoxib derivative 15.1 can be obtained as described in U.S. Pat. No.5,633,272 Example 1. Compound 15.1 is dissolved in a suitable solventsuch as, for example, DCM and is treated with AlCl₃ and a suitableanhydride, for example, succinic anhydride as described in Tett. Lett 42(2001) 1467-1469. The acylated products are purified using reverse phaseHPLC or flash chromatography on silica gel to give carboxylic acidderivatives 15.2, 15.3 and 15.4. Valdecoxib derivatives 15.2, 15.3 and15.4 are independently dissolved in a suitable solvent such as, forexample, DMF and treated with an amine phosphonic acid ester of thegeneral formula 15.5 in the presence of a suitable coupling reagant andtertiary organic base to afford the amides 15.6, 15.7, and 15.8.

EXAMPLE 16 Synthesis of Representative Compounds of Formula 12

Compound 16.2, 16.3, or 16.4 dissolved in DMF, is treated with 3equivalents of (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PYBOP, Sigma) and 6 equivalents ofdiisopropylamine. The activated esters of 16.2, 16.3 and 16.4 are thenindependently treated with 3 equivalents of the hydrochloride salt ofdiethyl 2-aminoethyl-1-phosphonate 16.6 which is prepared as describedin J. Med. Chem 41 4439-4452. The final products are purified by reversephase or flash chromatography on silica gel to give amides 16.7, 16.8and 16.9. Using the above procedure but employing different phosphonatereagants in the place of 16.6 additional compounds of the invention canbe prepared.

EXAMPLE 17 Synthesis of Representative Compounds of Formula 13

Intermediate 17.1 is prepared as described in U.S. Pat. No. 4,076,709example 9 or as described in J. Med. Chem. 30 678-682 1987. Intermediate17.1 is converted to intermediate 17.2 using the appropriatelysubstituted aminonicotinic acid. Intermediate 17.2 is treated with anamine phosphonic acid ester of the general formula 17.3 in the presenceof a suitable coupling reagant and tertiary organic base to afford theamides 17.4, 17.5 and 17.6.

EXAMPLE 18 Synthesis of Representative Compounds of Formula 13

Compound 18.1 and 6-aminonictonic acid are dissolved in a suitablesolvent such as xylene and refluxed with active carbon to giveintermediate 18.5. which is purified by reverse phase or normal phasechromatography. Tenoxicam derivative 18.5 is then dissolved in anhydrousDMF and treated with 3 equivalents ofO-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexaflurophosphate (Sigma) and 6 equivalents of diisopropylethylamine.The activated ester of 18.5 is then treated with 3 equivalents of thehydrochloride salt of diethyl 2-aminoethyl-1-phosphonate 18.6 which isprepared as described in J. Med. Chem 41 4439-4452 to give compound 18.7which is purified by reverse phase or normal phase chromatography. Usingthe above procedure but employing different phosphonate reagants in theplace of compound 18.6 additional compounds of the invention can beprepared.

EXAMPLE 19 Synthesis of Representative Compounds of Formula 16 ans 17

Celecoxib derivative 19.1 can be obtained as described in U.S. Pat. No.5,466,823 Example (1 g). Compound 19.1 is dissolved in a suitablesolvent such as, for example, DCM and is then treated with AlCl₃ and asuitable anhydride, for example, succinic anhydride as described inTett. Lett 42 (2001) 1467-1469. The acylated products are purified usingreverse phase HPLC or flash chromatography on silica gel to givecarboxylic acid derivatives 19.2, 19.3, 19.4 and 19.5. Celecoxibderivatives 19.2, 19.3, 19.4 and 19.5 are independently dissolved in asuitable solvent such as, for example, DMF and treated with an aminephosphonic acid ester of the general formula 19.6 in the presence of asuitable coupling reagant and tertiary organic base to afford the amides19.7, 19.8, 19.9 and 19.10.

EXAMPLE 20 Synthesis of Representative Compounds of Formulae 16 and 17

Compound 20.2, 20.3, 20.4, or 20.5 dissolved in DMF, is treated with 3equivalents of (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PYBOP, Sigma) and 6 equivalents ofdiisopropylamine. The activated esters of 20.2, 20.3 20.4 and 20.5 arethen independently treated with 3 equivalents of the hydrochloride saltof diethyl 2-aminoethyl-1-phosphonate 20.7 which is prepared asdescribed in J. Med. Chem 41 4439-4452. The final products are purifiedby reverse phase or flash chromatography on silica gel to give amides20.8, 20.9, 20.10 and 20.11. Using the above procedure but employingdifferent phosphonate reagants in the place of 20.7 additional compoundsof the invention can be prepared.

EXAMPLE 21 Synthesis of Representative Compounds of Formula 18

Etodolac 21.1 can be purchased from Sigma (Cat. No. E0156) or obtainedas described in U.S. Pat. No. 3,939,178 Example 477. The indole 21.1 isdeprotonated with a suitably strong base such as, for example, KOH orK₂CO₃ in DMSO or DMF as described in J. Org. Chem 64 6102-6105, followedby alkylation with a halide phosphonic acid ester of the general formula21.2. The alkylated product is purified by reverse phase or flashchromatography on silica gel to give compound 21.3.

EXAMPLE 22 Synthesis of Representative Compounds of Formula 18

Compound 22.1 is dissolved in DMSO and treated with 6 equivalents ofpotassium hydroxide, followed by addition of 1.1 equivalents of 22.3which is prepared as described in J. Org. Chem, 52 4427. The residue ispurified using reverse-phase or normal phase chromatography to give 22.4Using the above procedure but employing different phosphonate reagantsin the place of compound 22.3 additional compounds of the invention canbe prepared.

EXAMPLE 23 Synthesis of Representative Compounds of Formula 19

Etoricoxib derivative 23.1 can be obtained as described in U.S. Pat. No.5,861,419 Example 59. Alternative syntheses for 23.1 are described in J.Org. Chem 2000, 65, 8415-8420. The 2-methyl group of the 5-pyridyl ringis deprotonated with a suitably strong base such as, for example, n-BuLiusing the procedure described in J. Org. Chem 1987, 52, 4227 followed byalkylation of the newly formed carbanion with a halide phosphonic acidester of the general formula 23.2. The alkylated product is purified byreverse phase or flash chromatography on silica gel to give compound23.3.

EXAMPLE 24 Synthesis of Representative Compounds of Formula 19

1.5 Equivalents of a 1.6 N solution of n-butyllithium in hexane is addedto a solution of compound 24.1 in anhydrous ethyl ether at 0° C. Thesolution is treated with 4 equivalents of compound 24.3 which isprepared as described in J. Org. Chem, 52 4427. The residue is purifiedusing reverse-phase or normal phase chromatography to give 24.4. Usingthe above procedure but employing different phosphonate reagants in theplace of compound 24.3 additional compounds of the invention can beprepared.

EXAMPLE 25 Synthesis of Representative Compounds of Formula 20

Ibuprofen (U.S. Pat. No. 3,385,886), commercially available fromSigm-Aldrich, is converted to dicaroxylic acids 25.2 and 25.3 by theaction of succinic anhydride in the presence of aluminum trichloride ina suitable solvent (carbon disulfide, nitrobenzene, dichloroethane).Covnersion 25.2 and 25.3 to phosphonate prodrugs occurs by the additionof 1.5 equivalents HOAT, HATU, diisoproplylethylamine to 25.2 and 25.3followed by the addition of 25.5 all in a suitable solvent such as NMP,DMF, THF, or dichloroethane. Separation of the final mixture leads tothe desired materials 25.6 and 25.7, 25.8 and 25.9.

EXAMPLE 26 Synthesis of Representative Compounds of Formulae 21 and 22

Naproxen (U.S. Pat. No. 3,904,683), commercially available fromSigm-Aldrich, is converted to dicaroxylic acids 26.2 and 26.3 by theaction of succinic anhydride in the presence of aluminum trichloride ina suitable solvent such as carbon disulfide, nitrobenzene, anddichloroethane. Conversion of 26.2 and 26.3 to phosphonate prodrugsoccurs by the addition of 1.5 equivalents HOAT, HATU, anddiisoproplylethylamine to 26.2 and 26.3 followed by the addition of 26.4all in a suitable solvent such as NMP, DMF, THF, or dichloroethane.Separation of the final mixture leads to the desired materials 26.5,26.6, 26.7, 26.8.

EXAMPLE 27 Synthesis of Representative Compounds of Formula 23

Loxoprofen (U.S. Pat. No. 4,400,534), commercially available fromSigm-Aldrich, is converted to dicaroxylic acids 27.2 and 27.3 by theaction of succinic anhydride in the presence of aluminum trichloride ina suitable solvent such as carbon disulfide, nitrobenzene, anddichloroethane. Conversion 27.2 and 27.3 to phosphonate prodrugs occursby the addition of 1.5 equivalents HOAT, HATU, anddiisoproplylethylamine to 27.2 and 27.3 followed by the addition of 27.4all in a suitable solvent such as NMP, DMF, THF, or dichloroethane.Separation of the final mixture leads to the desired materials 27.5,27.6, 27.7 and 27.8.

EXAMPLE 28 Synthesis of Representative Compounds of Formula 25

Representative compounds of the invention (28.1) are illustrated above.A linkage group is a portion of the structure that links twosubstructures, one of which is Diclofenac having the general formulaabove, the other a phosphonate moiety bearing the appropriate R and R₁groups. The linkage typically has at least one uninterrupted chain ofatoms other than hydrogen. The R and R₁ groups can be both natural andun-natural amino acid esters linked through the amine nitrogen, oralternatively, one of the groups can be substituted for oxygen linkedaryl, alkyl, aralkyl group. Alternatively one of the groups may be anoxygen linked aryl, alkyl, aralkyl group and the other lactate ester.

The preparation of a representative compound of the invention isillustrated below.

Compound 28.2 (available from Sigma-Aldrich) is reacted with 3equivalents of a strong base (for example, NaH, KH, NaHMDS, KHMDS, LDA)in a polar aprotic solvent (DMF, DMSO, NMP, DMA, THF) for a period of 1minute to 4 hours. To this mixture is added triflate 28.3. Afterstandard work-up and purification, 28.4 is formed.

EXAMPLE 29 Synthesis of Representative Compounds of Formula 26

Representative compounds of the invention (29.1) are illustrated above.A linkage group is a portion of the structure that links twosubstructures, one of which is Relafen having the general formula above,the other a phosphonate moiety bearing the appropriate R and R₁ groups.The linkage has at least one uninterrupted chain of atoms other thanhydrogen. The R and R₁ groups can be both natural and un-natural aminoacid esters linked through the amine nitrogen, or alternatively, one ofthe groups can be substituted for oxygen linked aryl, alkyl, aralkylgroup. Alternatively one of the groups may be an oxygen linked aryl,alkyl, aralkyl group and the other lactate ester.

The preparation of a representative compound of the invention isillustrated below.

Relafen (29.2, U.S. Pat. No. 4,106,179), commercially available fromSigm-Aldrich, is converted to carboxylic acids 29.3 and 29.4 by theaction of succinic anhydride in the presence of aluminum trichloride ina suitable solvent such as carbon disulfide, nitrobenzene, anddichloroethane. Conversion 29.3 and 29.4 to phosphonate prodrugs occursby the addition of 1.5 equivalents HOAT, HATU, anddiisoproplylethylamine to 29.3 and 29.4 followed by the addition of 29.5all in a suitable solvent such as NMP, DMF, THF, or, dichloroethane.This process can either occur after separation of 29.3 from 29.4 bystandard means or on the mixture of products. Separation of the finalmixture leads to the desired materials. 29.6 and 29.7.

EXAMPLE 30 Synthesis of Representative Compounds of Formula 28

Representative compounds of the invention (30.1) are illustrated above.A linkage group is a portion of the structure that links twosubstructures, one of which is Mefeamic Acid having the general formulaabove, the other a phosphonate moiety bearing the appropriate R and R₁groups. The linkage has at least one uninterrupted chain of atoms otherthan hydrogen. The R and R₁ groups can be both natural and un-naturalamino acid esters linked through the amine nitrogen, or alternatively,one of the groups can be substituted for oxygen linked aryl, alkyl,aralkyl group. Alternatively one of the groups may be an oxygen linkedaryl, alkyl, aralkyl group and the other lactate ester.

The preparation of a representative compound of the invention isillustrated below.

Mefeamic Acid (30.2, U.S. Pat. No. 3,138,636), available fromSigm-Aldrich, is converted to nitro derivatives 30.3, 30.4, and 30.5 bythe action of nitric acid in the presence of fuming sulfuric acid.Conversion of 30.3, 30.4, and 30.5 to the corresponding anilines (30.6,30.7, and 30.8) is performed by reductive amination with 30.12 under avariety of conditions (Zn/AcOH, SnCl2, H2/Pd/C) in the appropriatesolvents. The anilines are converted to 30.9, 30.10, and 30.11 by theaction of a suitable reducing agent (NaCNBH₃, NaHB(OAc)₃, or NaBH₄) allin a suitable solvents such as NMP, DMF, THF, EtOH or dichloroethane.The regioisomers can be separated using standard methods known in theart at the nitro, aniline, or phosphonate stages.

EXAMPLE 31 Synthesis of Representative Compounds of Formula 30 and 31

Representative compounds of the invention (31.1) are illustrated above.A linkage group is a portion of the structure that links twosubstructures, one of which is Nimesulide having the general formulaabove, the other a phosphonate moiety bearing the appropriate R and R₁groups. The linkage has at least one uninterrupted chain of atoms otherthan hydrogen. The R and R₁ groups can be both natural and un-naturalamino acid esters linked through the amine nitrogen, or alternatively,one of the groups can be substituted for oxygen linked aryl, alkyl,aralkyl group. Alternatively one of the groups may be an oxygen linkedaryl, alkyl, aralkyl group and the other lactate ester.

The preparation of a representative compound of the invention isillustrated below.

Nimesulide (31.2, U.S. Pat. No. 3,840,597), available from Sigm-Aldrich,is converted to dicaroxylic acids 31.3, 31.4, and 31.5 by the action ofsuccinic anhydride in the presence of a Lewis acid such as aluminumtrichloride in a suitable solvent such as carbon disulfide,nitrobenzene, and dichloroethane. The products are separated by standardmethods or carried through to the next step after work-up. Conversion of31.3, 31.4, and 31.5 to phosphonate prodrugs occurs by the addition of1.5 equivalents HOAT, HATU, and diisoproplylethylamine to 31.3, 31.4,and 31.5 followed by the addition of 31.6 all in a suitable solvent suchas NMP, DMF, THF, or dichloroethane. Separation and/or purification ofthe final mixture produces to the desired materials 31.7, 31.8, and31.9.

EXAMPLE 32 Synthesis of Representative Compounds of Formula 32

Aspirin (32.1), available from Sigma-Aldrich, is converted todicarboxylic acids 32.2, 32.3, and 32.4 by the action of succinicanhydride in the presence of a Lewis acid such as aluminum trichloridein a suitable solvent (carbon disulfide, nitrobenzene, dichloroethane).Conversion 32.2, 32.3, and 32.4 to phosphonate prodrugs occurs by theaddition of 1.5 equivalents HOAT, HATU, diisoproplylethylamine to 32.2,32.3, and 32.4 followed by the addition of 32.5 all in a suitablesolvent such as NMP, DMF, THF, or dichloroethane. Separation usingstandard methonds of the final mixture leads to the desired materials32.6, 32.7, and 32.8, 32.9, 32.10, and 32.11. Alternatively, 3.1, 3.2,and 3.3 can be separated using standard methods and carried forward.

EXAMPLE 33 Synthesis of Representative Compounds of Formulae 33 and 34

Oxaprozin (33.1, U.S. Pat. No. 3,578,671), available from Sigma-Aldrich,is converted to carboxylic acids 33.2, 33.3, 33.4, 33.5, 33.6, and 33.7by the action of succinic anhydride in the presence of a Lewis acid suchas aluminum trichloride in a suitable solvent such as carbon disulfide,nitrobenzene, or dichloroethane. Conversion 33.2, 33.3, 33.4, 33.5,33.6, and 33.7 to phosphonate prodrugs occurs by the addition of 1.5equivalents HOAT, HATU, and diisoproplylethylamine 33.2, 33.3, 33.4,33.5, 33.6, and 33.7 followed by the addition of 33.8 all in a suitablesolvent such as NMP, DMF, THF, or dichloroethane. This process caneither occur after separation of 33.2, 33.3, 33.4, 33.5, 33.6, and 33.7by standard means or on the mixture of products. Separation of the finalmixture leads to the desired materials 33.9, 33.10, 33.11, 33.12, 33.13,and 33.14.

EXAMPLE 34 Synthesis of Representative Compounds of Formulae 35 and 36

Starting material 34.1 (U.S. Pat. No. 4,347,186) is combined separatelywith amino phosphonates 34.2, 34.3, 34.4, 34.5, and 34.6 by the action aweak base (for example, diisopropyl ethyl amine, triethyl amine,potassium carbonate, sodium carbonate) in a suitable polar solvent suchNMP, DMF, or DMSO and heated between 40 and 200° C. for a period between30 minutes and 2 weeks. Products are isolated and purified usingstandard protocols. Single enantiomers of 34.7, 34.8, 34.9, 34.10, and34.11 can be prepared as set out in U.S. Pat. No. 4,089,969, page 19paragraph 10. These resolved intermediates can be carried through aswith the linked Toradol compounds to form linked forms of (R)-Ketorolac.Alternatively, resolution of the enantiomers can occur at the 34.2,34.3, 34.4, 34.4, 34.5, and 34.6 stage in analogy to U.S. Pat. No.4,089,969.

EXAMPLE 35 Synthesis of Representative Compounds of Formulae 37-40

Representative phosphonate compounds of formulae 37-40 can be preparedfrom the compounds described by J. H. Fried et al., J. Am. Chem. Soc.,1963, 85, 236-238 and R. Hirschmann et al., J. Am. Chem. Soc., 1964, 86,1521-1527 using techniques similar to those described herein.

EXAMPLE 36 Synthesis of Representative Pimecrolimus Analogs of Formula41

In the following illustration the chloro substituted ring ofpimecrolimus is replaced by the group

and the remainder of the molecule is not shown in the illustration,although it is understood that the remainder of the molecule is present.

Ascomycyn, a synthetic precursor of pimecrolimus, is O-arylated as shownabove using an appropriate aryl bismuth reagent according to a proceduresuch as that reported in Bioorg. Med. Chem. Lett, 1995, 5, 1035.3-(Dimethyl-t-butylsilyloxy)bromobenzene is treated either withmagnesium in diethyl ether or with butyllithium in tetrahydrofuran, andthe resulting organometallic reagent is reacted with bismuth trichlorideto generate the triarybismuthine. After treating with 1-1.2 equivalentsof peracetic acid, the bismuth(V) reagent is mixed with ascomycin andcopper(II) acetate. The reaction is allowed to proceed for a day at roomtemperature or, if necessary, at reflux, affording the desired3-(dimethyl-t-butylsilyoxy)phenyl ether. After removal of thedimethyl-t-butylsilyl protecting group, O-akylation is achieved withdiethyl (bromomethyl)phosphonate in the presence of silver oxide,affording the desired pimecrolimus analog containing adiethylphosphonate 36.3. Silver ion-assisted reactions have been used tomediate O-alkylations of ascomycin: see J. Med. Chem., 1998, 41, 1764.

EXAMPLE 37 Synthesis of Representative Pimecrolimus Analogs of Formula41

In the following illustration the chloro substituted ring ofpimecrolimus is replaced by the group

and the remainder of the molecule is not shown in the illustration,although it is understood that the remainder of the molecule is present.

A phosphonate derivative of pimecrolimus indolyl ether is prepared asillustrated above, in a similar manner to that described in Example 36,with the exception that the key triindolylbismuthine intermediate isobtained from 5-bromoindole following the procedure described in J. Org.Chem. 1998, 63, 6721.

EXAMPLE 38 Synthesis of Representative Everolimus Analog of Formula 42

Rapamycin (compound 38.1 wherein the remaining portion of the rapamycinstructure is not shown), a synthetic precursor of everolimus, isO-arylated as shown above using an appropriate aryl bismuth reagentaccording to a procedure such as that reported in Bioorg. Med. Chem.Lett, 1995, 5, 1035. 3-(Dimethyl-t-butylsilyloxy)bromobenzene is treatedeither with magnesium in diethyl ether or with butyl lithium intetrahydrofuran, and the resulting organometallic reagent is reactedwith bismuth trichloride to generate the triarybismuthine. Aftertreating with 1-1.2 equivalents of peracetic acid, the bismuth(V)reagent is mixed with rapamycin and copper(II) acetate. The reaction isallowed to proceed for a day at room temperature or, if necessary, atreflux, affording the desired 3-(dimethyl-t-butylsilyloxy)phenyl ether38.2. After removal of the dimethyl-t-butylsilyl protecting group,O-akylation is achieved with diethyl (bromomethyl)phosphonate in thepresence of silver oxide, affording the desired everolimus analogcontaining the diethylphosphonate 38.3. Silver ion-assisted reactionshave been used to mediate O-alkylations on an immunosuppresive macrolidestructurally similar to rapamycin: see J. Med. Chem., 1998, 41, 1764.

EXAMPLE 39 Synthesis of Representative Everolimus Analog of Formula 42

A phosphonate derivative of everolimus indolyl ether is prepared fromrapamycin (formula 39.1 wherein the remaining portion of the rapamycinstructure is not shown) in a similar manner to that described in Example38, with the exception that the key triindolylbismuthine intermediate isobtained from 5-bromoindole following the procedure described in J. Org.Chem. 1998, 63, 6721.

EXAMPLE 40 Synthesis of Representative Sirolimus Analogs of Formula 42

Sirolimus is O-arylated as shown above using an appropriate aryl bismuthreagent according to a procedure such as that reported in Bioorg. Med.Chem. Lett, 1995, 5, 1035. 3-(Dimethyl-t-butylsilyloxy)bromobenzene istreated either with magnesium in diethyl ether or with butyllithium intetrahydrofuran, and the resulting organometallic reagent is reactedwith bismuth trichloride to generate the triarybismuthine. Aftertreating with 1-1.2 equivalents of peracetic acid, the bismuth(V)reagent is then mixed with sirolimus and copper(II) acetate. Thereaction is allowed to proceed for a day at room temperature or, ifnecessary, at reflux, affording the desired3-(dimethyl-t-butylsilyloxy)phenyl ether. After removal of thedimethyl-t-butylsilyl protecting group, O-akylation is achieved withdiethyl (bromomethyl)phosphonate in the presence of silver oxide,affording the desired sirolimus analog containing thediethylphosphonate. Silver ion-assisted reactions have been used tomediate O-alkylations on an immunosuppresive macrolide structurallysimilar to sirolimus: see J Med. Chem., 1998, 41, 1764.

EXAMPLE 41 Synthesis of Representative Sirolimus Analogs of Formula 42

A sirolimus indolyl ether is prepared as illustrated above, in a similarmanner to that described in Example 40, with the exception that the keytriindolylbismuthine intermediate is obtained from 5-bromoindolefollowing the procedure described in J. Org. Chem. 1998, 63, 6721.

EXAMPLE 42 Synthesis of Representative Compounds of Formula 45

Representative compounds of the invention can be prepared as illustratedabove. The preparation of a specific compound of the invention isdescribed below.

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604). When theactivation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed the solvent is removed in vacuo and the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventlike diethyl ether or the like.

EXAMPLE 43 Synthesis of Representative Compounds of Formula 45

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984,27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett., 1986,27, 1477) is added. After consumption of the activated species isobserved the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

EXAMPLE 44 Synthesis of Representative Compounds of Formula 46

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604.). Whenthe activation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoicacid is added. After consumption of the activated species is observedthe solvent is removed in vacuo and the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

EXAMPLE 45 Synthesis of Representative Compounds of Formula 47

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 1995, 117, 10879-10888) is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith trifluoroacetic acid (TFA). The product is isolated viachromatography after removal of the solvents. Alternatively, the productcan be isolated through precipitation form the reaction solution with anorganic solvent like diethyl ether or the like.

EXAMPLE 46 Synthesis of Representative Compounds of Formula 48

Representative compounds of the invention can be prepared as illustratedabove. Sulfonylation is conveniently carried out by reaction of theaniline with a sulfonyl chloride in the presence of a base such astriethylamine (J. Med. Chem., 1995, 38, 4897) in a solvent such asdichloromethane. Either one equivalent or an excess of the sulfonylchloride may be used; in the latter case, the bis-sulfonamide may beformed, in which case hydrolysis to the monosulfonamide is achievedthrough reaction with sodium hydroxide.

A sulfonylating reagent that can be used in the above procedure can beprepared as follows.

(3-Bromo-propyl)-phosphonic acid diethyl ester is treated with sodiumsulfide in a solvent such as ethanol, and the thiol produced is oxidizedwith chlorine in an aqueous solvent system to give the sulfonyl chloride(see Gilbert, ‘Sulfonylation and Related Reactions, Interscience, NewYork, 1965, pp 202-214).

EXAMPLE 47 Synthesis of Representative Compounds of Formula 49

The starting chloromethyl compound (see J. Med. Chem., 2000, 43, 775)serves as a useful intermediate for the introduction of a phosphonatemoiety at the methyl substituent of the isoxazole. After this isachieved, the sulfonamide group is introduced by the same methods as forvaldecoxib itself.

Optionally, the parecoxib-style prodrug may be formed by acylation ofthe sulfonamide using propionic anhydride and a base such astriethylamine, followed by formation of the sodium salt with sodiumhydroxide (see J. Med. Chem., 2000, 43, 1661).

A representative compound of the inveition can be prepared as follows.

The chloromethyl compound (see J. Med. Chem., 2000, 43, 775) is treatedwith a dehydrating reagent such as phosphorus oxychloride in thepresence of a base such as pyridine, optionally in a solvent such asdichloromethane. The (5-chloromethyl)isoxazole so formed is then treatedin a solvent such as tetrahydrofuran or dimethylformamide with a basesuch as sodium hydride. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986,27, 1477) is added, yielding the desired phosphonate diester.Sulfonylation with chlorosulfonic acid, quenching the resulting sulfonylchloride with ammonium hydroxide (according to J. Med. Chem., 2000, 43,775) gives the desired product.

EXAMPLE 48 Synthesis of Representative Compounds of Formula 51

Repersentative compounds of the invention can also be prepared asillustrated above. For example, a specific compound of the invention canbe prepared as follows.

The deoxybenzoin derivative bearing a phosphonate moiety (formed fromcommercially available 2-(4-methoxyphenyl)acetophenone by demethylationwith hydrobromic acid in acetic acid, and subsequent alkylation withdiethyl phosphonomethyltriflate (prepared according to TetrahedronLett., 1986, 27, 1477) in the presence of a base such as potassiumcarbonate in a solvent such as dimethylformamide) is subjected to thesame transformations as those outlined in J. Med. Chem., 2000, 43, 775to provide the phosphonate compound of the invention.

EXAMPLE 49 Synthesis of Representative Compounds of Formula 53

Representative compounds of the invention can be prepared as illustratedabove. Sulfonylation is conveniently carried out by reaction of theaniline with a sulfonyl chloride in the presence of a base such astriethylamine (J. Med. Chem., 1995, 38, 4897) in a solvent such asdichloromethane. Either one equivalent or an excess of the sulfonylchloride may be used; in the latter case, the bis-sulfonamide is formed,and hydrolysis to the monosulfonamide is achieved through reaction withsodium hydroxide. For example, a specific compound of the invention canbe prepared as follows.

(3-Bromo-propyl)-phosphonic acid diethyl ester is treated with sodiumsulfide in a solvent such as ethanol, and the thiol produced is oxidisedwith chlorine in an aqueous solvent system to give the sulfonyl chloride(see Gilbert, ‘Sulfonylation and Related Reactions, Intrscience, NewYork, 1965, pp 202-214). This reagent is used in the sulfonylationreaction described above to provide the representative compound of theinvention.

EXAMPLE 50 Synthesis of Representative Compounds of Formulae 52 and 54

Representative compounds of the invention can be prepared as illustratedabove. The phosphonate moiety may be attached to the central phenylring. If it is linked at the position para- to the sulfonylamideresidue, the linker should optimally exert an electron-withdrawingeffect to maximize the COX-2 inhibitory activity (see J. Med. Chem.,1995, 38, 4897). For example, a specific compound of the invention canbe prepared as follows.

3-Fluoro-4-nitrobenzoic acid is esterified by heating briefly in acidicmethanol. Treatment with phenol in a solvent such as dimethylformamidein the presence of a base such as potassium carbonate causesdisplacement of the fluoride and generation of the bis-aryl ether.Subsequent saponification of the benzoate ester with lithium hydroxidein a solvent such as tetrahydrofuran gives the free acid, which iscoupled with 2-aminoethylphosphonic acid diethyl ester (commerciallyavailable) using standard reagents for the formation of a secondaryamide such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole(HOBT), in a solvent such as dimethylformamide.

EXAMPLE 51 Synthesis of Representative Compounds of Formula 55

Representative compounds of the invention can be prepared as illustratedabove. The diaryl ether is conveniently formed using the Ullman method(Russ. Chem. Rev., 1974, 43, 679), catalyzed by copper (I) salts. Usingthis method, a phenol already bearing a phosphonate moiety may be usedto generate the desired analog efficiently. For example, a specificcompound of the invention can be prepared as follows.

2-Bromo-4-nitroaniline is sulfonylated in a manner similar to thatdescribed in example 49. The subsequent Ullman ether synthesis using(3-hydroxy-phenoxymethyl)phosphonic acid diethyl ester (formed by thereaction of resorcinol and diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 1986, 27, 1477) in the presence of abase such as magnesium t-butoxide gives the desired product.

EXAMPLE 52 Synthesis of Representative Compounds of Formula 56

Representative compounds of the invention can be prepared as illustratedabove. Final compounds, be they diastereoisomers or enantiomers, maytypically be purified by chromatographic means. In case a directcoupling to aminopterin is hampered by the presence of a free secondaryamine in the starting material (R=H), this entity is temporarilyprotected either with a tert.butoxycarbonyl group (R=Boc) orbenzyloxycarbonyl (R=Cbz or Z) according to standard procedures (GreenWutts: Protective groups in organic chemistry)

EXAMPLE 53 Synthesis of Representative Compounds of Formula 56

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604). When theactivation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed the solvent is removed in vacuo and the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventsuch as diethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed by filtration and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

EXAMPLE 54 Synthesis of Representative Compounds of Formula 56

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984,27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett., 1986,27, 1477) is added. After consumption of the activated species isobserved the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed by filtration and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

EXAMPLE 55 Synthesis of Representative Compounds of Formula 57

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604.). Whenthe activation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoicacid is added. After consumption of the activated species is observedthe solvent is removed in vacuo and the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent such asdiethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed.

The Pd/C is removed by filtration and the solvent is evaporated invacuo. The product is isolated via chromatography. Alternatively, theproduct can be isolated through precipitation from the reaction solutionwith an organic solvent such as diethyl ether or the like.

EXAMPLE 56 Synthesis of Representative Compounds of Formula 58

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 1995, 117, 10879-10888) is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventsuch as diethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed and the solvent is evaporated in vacuo.The product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like.

EXAMPLE 57 Synthesis of Representative Compounds of Formula 59

Representative compounds of the invention can be prepared as illustratedabove. The construction of the lumiracoxib core proceeds according tothe procedures described in WO-00123346. For example, a specificcompound of the invention can be prepared as follows.

Bromination (by standard methods—see de la Mare, ‘ElectrophilicHalogenation’, Cambridge University Press, London, 1976) ofm-tolyloxymethylphosphonic acid diethyl ester (formed from commerciallyavailable 3-methylphenol by alkylation with diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986,27, 1477) in the presence of a base such as potassium carbonate) gives amixture of isomers that are separated by chromatography, each of whichis potentially useful in the synthesis of analogs containing phosphonatemoieties linked to different positions of the phenyl ring in question.Subsequent steps proceed as described in WO-00123346, yieldingultimately a phosphonic acid analog of lumiracoxib. The key step is thecoupling of the aryl bromide and 2-chloro-5-fluoroaniline, catalyzed bya palladium (II) salt, typically with sodium t-butoxide as base (seeAngew. Chem. Int. Ed., 1998, 37, 2046-2067).

EXAMPLE 58 Synthesis of Representative Compounds of Formula 60

Representative compounds of the invention can be prepared as illustratedabove. This route to lumiracoxib analogs is described in WO-09911605,and relies on a copper-catalyzed step for forming the bis-aryl aminewith the phenyl acetic acid side chain already in place on one of thereagents. The phosphonate-bearing moity is conveniently introduced afterthis step, which typically requires heating (e.g. in xylenes). Forexample, a specific compound of the invention can be prepared asfollows.

The product of coupling betweenN,N-dimethyl-5-methyl-2-iodophenylacetamide and2-chloro-6-fluoro-5-nitroaniline is subjected to reduction understandard conditions such as treatment with tin(II) chloride orhydrogenation over palladium on charcoal. The resulting primary anilineis coupled with (diethoxy-phosphoryl)acetic acid (commerciallyavailable) in the presence of a reagent such asbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP®) to provide the compound of the invention.

EXAMPLE 59 Synthesis of Representative Compounds of Formula 61

Representative compounds of the invention can be prepared as illustratedabove. This route is analogous to that described in Example 57. Aspecific compound of the invention can be prepared as follows.

(4-Bromo-phenoxymethyl)phosphonic acid diethyl ester (formed fromcommercially available 4-bromophenol by alkylation with diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986,27, 1477) in the presence of a base such as potassium carbonate) servesa suitable starting material for an analog bearing a phosphonate linkedat the position shown, using chemistry analagous to that described inExample 57 above.

EXAMPLE 60 Synthesis of Representative Compounds of Formula 62

Representative compounds of the invention can be prepared as illustratedabove. The phosphonate-bearing moity may be attached to the carboxylateresidue of lumiracoxib using a derivative such as an acylsulfonamide topreserve the acidic nature of the group. For example, a specificcompound of the invention can be prepared as follows.

(3-Bromo-propyl)-phosphonic acid diethyl ester is treated with sodiumsulfide in a solvent such as ethanol, and the thiol produced is oxidizedwith chlorine in an aqueous solvent system to give the sulfonyl chloride(see Gilbert, ‘Sulfonylation and Related Reactions, Interscience, NewYork, 1965, pp 202-214). This reagent is treated briefly with ammoniumhydroxide to generate the sulfonamide, which is condensed with the acidchloride of lumiracoxib (generated by treatment of lumiracoxib withthionyl chloride is a solvent such as diochloromethane), yielding thecompound of the invention.

EXAMPLE 61 Synthesis of Representative Tacrolimus Analog of Formula 63

Tacrolimus (compound 61.1 wherein the remaining portion of thetacrolimus molecule is not shown) is O-arylated as shown above using anappropriate aryl bismuth reagent according to a procedure such as thatreported in Bioorg. Med. Chem. Lett, 1995, 5, 1035.3-(dimethyl-t-butylsilyloxy)bromobenzene is treated either withmagnesium in diethyl ether or with butyllithium in tetrahydrofuran, andthe resulting organometallic reagent is reacted with bismuth trichlorideto generate the triarybismuthine. After treating with 1-1.2 equivalentsof peracetic acid, the bismuth(V) reagent is mixed with tacrolimus 61.1and copper(II) acetate. The reaction is allowed to proceed for a day atroom temperature or, if necessary, at reflux, affording the desired3-(dimethyl-t-butylsilyloxy)phenyl ether. After removal of thedimethyl-t-butylsilyl protecting group with HF, O-akylation is achievedwith diethyl (bromomethyl)phosphonate in the presence of silver oxide,affording the desired tacrolimus analog containing thediethylphosphonate 61.3. Silver ion-assisted reactions have been used tomediate O-alkylations on an immunosuppresive macrolide structurallysimilar to tacrolimus: see J. Med. Chem., 1998, 41, 1764.

EXAMPLE 62 Synthesis of representative Tacrolimus Analog of Formula 63

A phosphonate derivative of tacrolimus indolyl ether is prepared fromtacrolimus (compound 62.1 wherein the remaining portion of thetacrolimus molecule is not shown) in a similar manner to that describedin Example 61 with the exception that the key triindolylbismuthineintermediate is obtained from 5-bromoindole following the proceduredescribed in J. Org. Chem. 1998, 63, 6721.

EXAMPLE 63 Synthesis of Representative Compounds of Formulae 64 and 65

Representative compounds of the invention can be made by procedures suchas those described by Boer, et al, J. Mass Spectrom. 1995, 30, 497-504and Hoyte, et al, J. Med. Chem. 2002, 45, 5397-5405, or they can be madeaccording to the general routes outlined above.

EXAMPLE 64 Synthesis of Representative Compounds of Formula 64

Prednisolone is treated in a solvent such as chloroform withformaldehyde in the presence of an acid such as concentratedhydrochloric acid. After stirring for several hours (preferably 7 to 10hours) at room temperature, the layers are separated and the organiclayer is concentrated to afford the bis-(methylenedioxy) intermediate(Hirschmann, R. et al, J. Am. Chem. Soc. 1964, 86, 1520-1527). Thisintermediate is treated with diethyl (aminooxymethyl)phosphonate in asolvent such as pyridine to afford the oxime, which is then treated withaqueous acid to remove the bis-(methylenedioxy) protecting group Forexample, the oxime is treated with 60% aqueous formic acid and heated at90° C. for 10 min., cooled and concentrated using portions of ethanol toassist in removing formic acid. Chromatographic purification and/orcrystallization of the residue yield the phosphonate oxime analog ofprednisolone. A key precursor of this synthesis, diethyl(aminooxymethyl)-phosphonate, can be obtained from diethyl(trifluoromethylsulfonyloxymethyl)-phosphonate andN-(t-butoxycarbonyl)-hydroxylamine. Accordingly,N-(t-butoxycarbonyl)hydroxylamine is dissolved in a solvent such as THFand treated with sodium hydride. When bubbling ceases, diethyl(trifluoromethyl-sulfonyloxymethyl)phosphonate (prepared according toTetrahedron Lett., 1986, 27, 1477) is added. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the N-Boc protected diethyl(aminooxymethyl)phosphonate is isolated by chromatography. The N-Bocprotecting group is then removed by treatment of trifluoroacetic acid,affording the desired diethyl (aminooxymethyl)phosphonate.

EXAMPLE 65 Synthesis of Representative Compounds of Formula 65

A phosphonate pyrazole analog of prednisolone can be prepared asillustrated above. Prednisolone is reduced to 1,2-dihydroprednisoloneusing a rhodium catalysis such as tris(triphenylphosphine)rhodium(I)chloride under hydrogen according to a procedure such as that reportedby Procopiou, P. et al, J. Med. Chem. 2001, 44, 602-612. The dihydroxyketone group on the D ring of the steroid is then protected using themethod described in Example 64, before formylation at the C-2 position.For example, the bis-(methylenedioxy) intermediate is treated withfreshly distilled ethyl formate and sodium hydride in a solvent such astoluene. The reaction is quenched with aqueous solution of a weak basesuch as potassium dihydrogen phosphate. The crude product is purified bya general method such as crystallization, affording the 2-formylintermediate. This 2-formyl compound is condensed with aphosphonate-substituted phenylhydrazine to yield, after removal of thebis-(methylenedioxy) protecting group, the desired phosphonate pyrazoleanalog of prednisolone. A key precursor,3-[(diethylphosphono)methoxy]phenylhydrazine, can be made starting fromdiethyl (trifluoromethylsulfonyloxymethyl)phosphonate and 3-nitrophenol.3-Nitrophenol is treated with a base such as sodium hydroxide and thenO-alkylated with diethyl (trifluoromethylsulfonyloxymethyl)phosphonate.The nitro group is reduced with tin(II) chloride and subsequentlyconverted to the aryl hydrazine by diazotization and reduction withsodium sulfite (Chem. Ber., 1960, 93, 540) or tin(II) chloride (J. Med.Chem., 2001, 44, 4031).

EXAMPLE 66 Synthesis of Representative Compounds of Formula 67

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 67 can be prepared asfollows.

The primary amide in CC-1088 can be acylated with (BOC)₂O usingN,N-dimethylaminopyridine as a base in a solvent such astetrahydrofuran. Subsequent condensation with 3-aminopropylphosphonicacid diethyl ester in a solvent such as tetrahydrofuran gives thedesired compound.

EXAMPLE 67 Synthesis of Representative Compounds of Formula 68

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 68 can be prepared asfollows.

The chloride is made from (3-cyclopentyloxy-4-methoxyphenyl)phenylketone(U.S. Pat. No. 5,622,977) by reduction with sodium borohydride inethanol and treatment of the resulting alcohol with triphenylphosphine,carbon tetrachloride and diisopropyl azodicarboxylate in a solvent suchas tetrahydrofuran. The condensation is achieved by treatment of the tworeagents with sodium ethoxide in ethanol. The ethyl ester in the productis saponified by treatment with lithium hydroxide in ethanol, and theresulting acid is decarboxylated by heating under acidic conditions. Thetwo enantiomers of the product may be separated by chromatography.

The synthesis of a pyridine intermediate is illustrated below.

(2-Oxo-1,2-dihydro-pyridin-4-yl)-acetic acid ethyl ester is treated witha base such as sodium hydride in a solvent such as tetrahydrofuran.After bubbling ceases, an excess of 1,3-dibromopropane is added. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, the mono-bromideis isolated by chromatography. The bromide is then heated withtriethylphosphite in a solvent such as toluene to generate the diethylester of the desired phosphonic acid.

EXAMPLE 68 Synthesis of Representative Compounds of Formula 69

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 69 can be prepared asfollows.

Cilomilast can be converted to its acid chloride by treatment withoxalyl chloride in dimethylformamide. The acid chloride is then coupledwith 2-aminoethylphosphonic acid diethyl ester in the presence of a basesuch as triethylamine in a solvent such as dichloromethane to generatethe desired compound.

EXAMPLE 69 Synthesis of Representative Compounds of Formula 70

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 70 can be prepared asfollows.

The carboxylic acid of cilomilast can be reduced to the alcohol bytreatment with diborane in a solvent such as tetrahydrofuran. Thealcohol is converted to the bromide by treatment with carbontetrabromide and triphenylphosphine in a solvent such as tetrahydrofuranor dichloromethane. The bromide is then heated with triethylphosphite ina solvent such as toluene to generate the diethyl ester of thephosphonic acid.

EXAMPLE 70 Synthesis of Representative Compounds of Formula 71

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 71 can be prepared asfollows.

1,3-Dihydroxypropane is treated with a base such as sodium hydride in asolvent such as tetrahydrofuran. After bubbling ceases, the2,3,5-trichloropyridyl analog of piclamilast (made by methods analogousto those described in U.S. Pat. No. 5,698,711) is added. After quenchingthe reaction with aqueous ammonium chloride and extracting the productwith an organic solvent such as ethyl acetate, the mono-alkylatedalcohol is isolated by chromatography. The alcohol is converted to thebromide by treatment with carbon tetrabromide, triphenylphosphine anddiisopropyl azodicarboxylate in a solvent such as tetrahydrofuran ordichloromethane. The bromide is then heated with triethylphosphite in asolvent such as toluene to generate the diethyl ester of the phosphonicacid.

EXAMPLE 71 Synthesis of Representative Compounds of Formula 72

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 72 can be prepared asfollows.

1,3-Dihydroxypropane is treated with a base such as sodium hydride in asolvent such as tetrahydrofuran. After bubbling ceases, the2,3,5-trichloropyridyl analog of roflumilast (made by methods analogousto those described in U.S. Pat. No. 5,712,298) is added. After quenchingthe reaction with aqueous ammonium chloride and extracting the productwith an organic solvent such as ethyl acetate, the mono-alkylatedalcohol is isolated by chromatography. The alcohol is converted to thebromide by treatment with carbon tetrabromide, triphenylphosphine anddiisopropyl azodicarboxylate in a solvent such as tetrahydrofuran ordichloromethane. The bromide is then heated with triethylphosphite in asolvent such as toluene to generate the diethyl ester of the phosphonicacid.

EXAMPLE 72 Synthesis of Representative Compounds of Formula 73

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 73 can be prepared asfollows.

Atizoram can be treated in a solvent such as dimethylformamide ortetrahydrofuran with a base such as sodium hydride. When bubblingceases, E-1,4-dibromobutene is added in excess. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the mono-alkylated product isisolated by chromatography. The allylic bromide is then heated withtriethylphosphite in a solvent such as toluene to generate the diethylester of the phosphonic acid.

Synthetic methodologies and intermediate compounds that can be used toprepare VX-148 analogs of formulae A, B, or C are described in Examples73-78. These compounds are representative examples of compounds ofFormulae 74, 75, and 76.

Link includes 0-8 atoms; 2-6 is preferred

EXAMPLE 73 General Synthesis of Aniline Intermediate Useful forPreparing VX-148 Analog of Formula A

A general scheme that is useful for converting a 3,5-difunctionalizednitrobenzene derivative to an aniline that can be used to prepare aVX-148 analog of the invention is illustrated above.

EXAMPLE 74 Synthesis of Aniline Intermediate Useful for Preparing VX-148Analog of Formula A

3-Hydroxy-5-nitro-benzoic acid is heated briefly in thionyl chloride togenerate the acid chloride. This is then condensed withO,N-dimethyl-hydroxylaamine in the presence of a base such astriethylamine to produce the Weinreb amide which, upon reaction withmethyl lithium, gives the acetophenone derivative. This is then treatedwith a base such as potassium carbonate in a dipolar aprotic solventsuch as dimethyl-formamide, in the presence of an excess ofE-1,4-dibromobutene. The monobromide is isolated by chromatography andthen subjected to treatment with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., Synthesisof carbon-phosphorus bonds, CRC press, 1988) to generate the desiredphosphonate diethyl ester. Thereafter, the carbonyl of the acetophenoneis reduced enantioselectively using an appropriate homochiraloxazaborolidine such as that described by Corey (J. Am. Chem. Soc.,1987, 109, 5551), and the resulting alcohol is displaced by azide usinga method such as that described by Mitsunobu (Bull. Chem. Soc. Japan.,1971, 44, 3427). The azide is reduced to the amine under Staudingerconditions (Helv. Chim. Act., 1919, 2, 635) and protected as the t-butylcarbonate. Finally, the desired aniline intermediate is generated by tin(II)-mediated reduction of the nitrobenzene.

EXAMPLE 75 Synthesis of VX-148 Analog of formula B

A general scheme that is useful for converting a 3,4-difunctionalizednitrobenzene derivative to an aniline, which can be converted to acompound of formula B using coupling reactions similar to thosedescribed in U.S. Pat. No. 6,054,472 and U.S. Pat. No. 6,344,465, isillustrated above.

EXAMPLE 76 General Route to Representative Compounds of Formula C

Manipulation of a 3-substituted nitrobenzene 76.1 provides aniline 76.2,which can be converted to a compound of formula C using couplingreactions similar to those described in U.S. Pat. No. 6,054,472 and U.S.Pat. No. 6,344,465.

EXAMPLE 77 General Route to Aniline Intermediate Useful For PreparingRepresentative Compounds of Formula C

3-Nitrobenzaldehyde reacts with a Grignard reagent to introduce a tetherbearing a protected alcohol and simultaneously to generate a benzylicalcohol, as shown. The alcohol is displaced by an azide in a mannersimilar to that described for Example 9. After deprotection, theliberated alcohol is alkylated with diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) using a basesuch as magnesium tert-butoxide in a solvent such as tetrahydrofuran.Subsequent transformations of the azide and nitro groups proceed in afashion similar to that described in Example 74. See Batt et al, Bioorg.Med. Chem. Lett., 1995, 5, 1549.

EXAMPLE 78 General Route to Aniline Intermediate Useful For PreparingRepresentative Compounds of Formula C

3-tert-Butoxycarbonylamino-3-(3-nitro-phenyl)-propionic acid(commercially available) is coupled with 2-aminoethylphosphonic aciddiethyl ester (commercially available) using standard reagents for theformation of a secondary amide such as dicyclohexylcarbodiimide (DCC)and hydroxybenztriazole (HOBT), in a solvent such as dimethylformamide.Subsequent reduction of the nitro group proceeds in a fashion similar tothat described in Example 74.

EXAMPLE 79 General Route to Representative Compounds of Formula 79

The following is a general route that can be used to prepare compoundsof Formula 79.

EXAMPLE 80 Preparation of a Representative Compound of Formula 77

The initial Pfitzinger condensation of compound 80.1 and compound 80.2is achieved in a single step using potassium hydroxide with acidicwork-up, as shown. Alternatively, the initial aldol condensation may beperformed using diethylamine in ethanol, and the quinoline ring may beformed as a second step mediated by an acid such as hydrochloric acid ina solvent such as 1,4-dioxane. Following removal of the benzylprotecting group via hydrogenation, the phenol can be treated in asolvent such as tetrahydrofuran or dimethylformamide with a base such assodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added,yielding the desired phosphonate diester. The carboxylate is deprotectedby treatment with lithium hydroxide in ethanol to provide the compound80.4 (which is a compound of formula 78).

EXAMPLE 81 Preparation of a Representative Brequinar Phosphonate Analogof Formula 80

The synthesis is similar to that depicted in Example 80 except that,following deprotonation of the phenol, E-1,4-dibromobutene is added inexcess. After quenching the reaction with aqueous ammonium chloride andextracting the product with an organic solvent such as ethyl acetate,the mono-alkylated product is isolated by chromatography. The resultingbromide is heated with triethylphosphite in a solvent such as toluene togenerate the diethyl ester of the desired phosphonic acid, and thecarboxylic acid is deprotected as before to provide a compound offormula 80.

EXAMPLE 82 Preparation of Representative Compound of Formula 81

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 81 can be prepared asfollows.

Diflunisal is converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Diflunisal is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the aniline(J. Org. Chem., 2002, 67, 6260). The aniline is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid is obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The aniline derived from diflunisal is converted to the aryl bromideusing a variant of the Sandmeyer reaction (Bull. Chem. Soc. Jpn., 1980,53, 1065). This is then coupled with pent-4-ynyl-phosphonic acid diethylester (generated from 5-chloro-1-pentyne and triethylphosphite in asolvent such as toluene, or other Arbuzov reaction conditions: seeEngel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988) underconditions such as those pioneered by Sonagashira (Sonogashira, K.;Tohda, Y.; Hagihara, N. Tetrahedron Lett., 1975, 4467) to afford thedesired diflunisal analog containing a phosphonate.

EXAMPLE 83 Preparation of Representative Compounds of Formula 82

Representative compounds of the invention can be prepared as illustratedabove. The aryl hydrazine is condensed with4,4-dimethyl-3-oxo-pentanenitrile to form an aminopyrazole (as describedin J. Med. Chem., 2002, 45, 2994). Urea formation is accomplished bysequential condensation with 4-nitrophenyl chloroformate and therequisite aniline. The latter is generated from 4-nitro-naphthalen-1-olby reaction with 2-morpholin-4-yl-ethanol using a method such as thatdescribed by Mitsunobu (Bull. Chem. Soc. Japan, 1971, 44, 3427),followed by tin(II)-mediated reduction of the nitro group to provide theaniline.

The synthesis of a suitable phosphonate-containing arylhydrazineintermediate is illustrated below.

5-Methyl-2-nitrophenol is alkylated with E-1,4-dibromobutene. Theresulting monobromide is heated with triethylphosphite in a solvent suchas toluene (or other Arbuzov reaction conditions: see Engel, R.,Synthesis of carbon-phosphorus bonds, CRC press, 1988) to generate thediethyl ester of the desired phosphonic acid. The nitro group isconverted to the aryl hydrazine by diazotization and reduction withsodium sulfite (Chem. Ber., 1960, 93, 540) or tin(II) chloride (J. Med.Chem., 2001, 44, 4031).

The syntheses of suitable phosphonate-containing aryl hydrazines inwhich link is attached to the 3- or 4-positions of the phenyl ring areanalogous to that shown in Example 83, starting from2-methyl-5-nitrophenol and 4-nitrophenol, respectively.

EXAMPLE 84 Preparation of Representative Compound of Formula 85

Representative compounds of the invention can be prepared as illustratedabove. Following the synthesis of the urea through condensation of5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine and1-isocyanato-4-methoxy-naphthalene, the product is demethylated bytreatment with a Lewis acid such as boron tribromide. The resultingphenol is coupled with a suitable morpholine derivative using a methodsuch as that described by Mitsunobu (Bull. Chem. Soc. Japan., 1971, 44,3427).

The synthesis of a suitable phosphonate-containing morpholineintermediate is illustrated below.

Morpholine-2,4-dicarboxylic acid 4-benzyl ester (generated frommorpholine-2,4-dicarboxylic acid by reaction with benzyl chloroformateunder standard protection conditions (such as those described in Greene,T., Protective groups in organic synthesis, Wiley-interscience, 1999))is coupled with 2-aminoethylphosphonic acid diethyl ester (commerciallyavailable) using standard reagents for the formation of a secondaryamide such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole(HOBT), in a solvent such as dimethylformamide. Removal of the benzylcarbamate protecting group by hydrogenation over palladium in a solventsuch as methanol (as described in Greene, T. ibid.) provides the desiredproduct.

EXAMPLE 85 Preparation of Representative Compounds of Formula 86

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 86 can be prepared asfollows.

Tolfenamic acid is converted to its acid chloride by treatment withoxalyl chloride in dimethylformamide. The acid chloride is then coupledwith 2-aminoethylphosphonic acid diethyl ester in the presence of a basesuch as triethylamine in a solvent such as dichloromethane to generatethe desired amide product.

Tolfenamic acid is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the aniline(J. Org. Chem., 2002, 67, 6260). The aniline is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid is obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The aniline derived from tolfenamic acid is converted to the arylbromide using a variant of the Sandmeyer reaction (Bull. Chem. Soc.Jpn., 1980, 53, 1065). This is then coupled with pent-4-ynyl-phosphonicacid diethyl ester (generated from 5-chloro-1-pentyne andtriethylphosphite in a solvent such as toluene, or other Arbuzovreaction conditions: see Engel, R., Synthesis of carbon-phosphorusbonds, CRC press, 1988) under conditions such as those pioneered bySonagashira (Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.,1975, 4467) to generate the desired phosphonate-containing analog oftolfenamic acid.

EXAMPLE 86 Preparation of Representative Compounds of Formula 87

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 87 can be prepared asfollows.

The methyl ester shown is treated in a solvent such as ethanol withexcess E-1,4-dibromobutene in the presence of a base such as sodiumhydroxide, as described in J. Med. Chem., 1997, 40, 980. The monobromideso formed is then heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., Synthesisof carbon-phosphorus bonds, CRC press, 1988) to generate the diethylester of the desired phosphonic acid. Heating with 2-aminopyridine insolvents such as xylenes, as described in J. Med. Chem., 1997, 40, 980,gives the desired piroxicam analogue, which is transformed to thecorresponding droxicam-like prodrug by treatment with phosgene and atertiary amine such as triethylamine in solvents such as tetrahydrofuranand/or benzene, as described in J. Med. Chem., 1973, 16, 44.

EXAMPLE 87 Preparation of Representative Compounds of Formula 88

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 88 can be prepared asfollows.

2-Amino-5-bromopyridine is coupled with pent-4-ynyl-phosphonic aciddiethyl ester (generated from 5-chloro-1-pentyne and triethylphosphitein a solvent such as toluene, or other Arbuzov reaction conditions: seeEngel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988) underconditions such as those pioneered by Sonagashira (Sonogashira, K.;Tohda, Y.; Hagihara, N. Tetrahedron Lett., 1975, 4467) to afford thedesired phosphonate-containing aminopyridine. This is then heated withthe methyl ester shown in solvents such as xylenes, as described in J.Med. Chem., 1997, 40, 980, to give the desired piroxicam analogue, whichis transformed to the corresponding droxicam-like prodrug by treatmentwith phosgene and a tertiary amine such as triethylamine in solventssuch as tetrahydrofuran and/or benzene, as described in J. Med. Chem.,1973, 16, 44.

EXAMPLE 88 Preparation of Representative Compounds of Formula 89

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 89 can be prepared asfollows.

Flurbiprofen is converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Flurbiprofen is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid is obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from flurbiprofen can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of flurbiprofen, according to a procedure such asthat reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 89 Preparation of Representative Compounds of Formula 90

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 90 can be prepared asfollows.

Indomethacin is converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Indomethacin is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from indomethacin can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of indomethacin, according to a procedure such asthat reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 90 Preparation of Representative Compounds of Formula 91

Compounds of the invention can be prepared as generally described inSchemes 1 and 2, with examples depicted in Examples 1 and 2.

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 91 can be prepared asfollows.

The methyl ester shown (made from the des-chloro compound (J. Med.Chem., 1987, 30, 678) by treatment with N-chlorosuccinimide in a solventsuch as dichloromethane) is treated in a solvent such as ethanol withexcess E-1,4-dibromobutene in the presence of a base such as sodiumhydroxide, as described in J. Med. Chem., 1997, 40, 980. The monobromideso formed is then heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., Synthesisof carbon-phosphorus bonds, CRC press, 1988) to generate the diethylester of the desired phosphonic acid. Finally, heating with2-aminopyridine in solvents such as xylenes, as described in J. Med.Chem., 1997, 40, 980, gives the desired analogue.

EXAMPLE 91 Preparation of Representative Compounds of Formula 92

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 92 can be prepared asfollows.

2-Amino-5-bromopyridine is coupled with pent-4-ynyl-phosphonic aciddiethyl ester (generated from 5-chloro-1-pentyne and triethylphosphitein a solvent such as toluene, or other Arbuzov reaction conditions: seeEngel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988) underconditions such as those pioneered by Sonagashira (Sonogashira, K.;Tohda, Y.; Hagihara, N. Tetrahedron Lett., 1975, 4467) to afford thedesired phosphonate-containing aminopyridine. This is then heated withthe methyl ester shown in solvents such as xylenes, as described in J.Med. Chem., 1997, 40, 980, to give the desired lomoxicam analogue.

EXAMPLE 92 Preparation of Representative Compounds of Formula 93

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 93 can be prepared asfollows.

4-Benzyloxyaniline is condensed with diethyl phosphonoacetic acidchloride (formed from diethyl phosphonoacetic acid by treatment withoxalyl chloride, in the presence of a catalytic amount ofdimethylformamide, in a solvent such as dichloromethane) in the presenceof a base such as triethylamine. The phenol is liberated byhydrogenation over a catalyst of palladium on charcoal according toGreene, Protective Groups in Synthesis, Wiley, 1999. This is thencondensed with succinic anhydride using a base such as sodium hydride ina solvent such as tetrahydrofuran (Bioorg. Med. Chem. Lett., 2002, 12,2545). The acid so formed is reduced with diborane in a solvent such astetrahydrofuran, and the resulting primary alcohol is reacted with thenitrating reagent shown in a solvent such as tetrahydrofuran (Helv.Chim. Act., 1984, 67, 906).

EXAMPLE 93 Preparation of Representative Compounds of Formula 94

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 94 can be prepared asfollows.

5-Hydroxyanthranilic acid is heated with acetic anhydride, generatingthe tri-acetylated species. This is then allowed to react with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thephosphonate-containing amide. Following deprotection of the phenol bytreatment with sodium ethoxide, the nitrate-containing side-chain isconstructed by initial condensation with succinic anhydride using a basesuch as sodium hydride in a solvent such as tetrahydrofuran (Bioorg.Med. Chem. Lett., 2002, 12, 2545), reduction of the acid so formed withdiborane in a solvent such as tetrahydrofuran, and finally reaction ofthe resulting primary alcohol with the nitrating reagent shown in asolvent such as tetrahydrofuran (Helv. Chim. Act., 1984, 67, 906).

EXAMPLE 94 Preparation of Representative Compounds of Formula 95

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 95 can be prepared asfollows.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984,27, 600-604). When the activation is complete, 2-aminoethylphosphonicacid diethyl ester (commercially available) is added. After consumptionof the activated species is observed the solvent is removed in vacuo andthe product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

EXAMPLE 95 Preparation of Representative Compound of Formula 95

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984,27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett., 1986,27, 1477) is added. After consumption of the activated species isobserved the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

EXAMPLE 96 Preparation of Representative Compound of Formula 96

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604.). Whenthe activation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoicacid is added. After consumption of the activated species is observedthe solvent is removed in vacuo and the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

EXAMPLE 97 Preparation of Representative Compound of Formula 97

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 1995, 117, 10879-10888) is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventlike diethyl ether or the like

EXAMPLE 98 Preparation of Representative Compound of Formula 98

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 98 can be prepared asfollows.

Niflumic acid is converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Niflumic acid is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the aniline(J. Org. Chem., 2002, 67, 6260). The aniline is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid is obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The aniline derived from niflumic acid is converted to the aryl bromideusing a variant of the Sandmeyer reaction (Bull. Chem. Soc. Jpn., 1980,53, 1065). This is then coupled with pent-4-ynyl-phosphonic acid diethylester (generated from 5-chloro-1-pentyne and triethylphosphite in asolvent such as toluene, or other Arbuzov reaction conditions: seeEngel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988) underconditions such as those pioneered by Sonagashira (Sonogashira, K.;Tohda, Y.; Hagihara, N. Tetrahedron Lett., 1975, 4467) to generate thedesired phosphonate-containing analog of niflumic acid.

EXAMPLE 99 Preparation of Representative Compounds of Formulae 99 and100

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 99 and 100 can beprepared as follows.

5-Nitro-isobenzofuran-1,3-dione (commercially available) is converted to5-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione following theprocedures reported in Bioorg. Med. Chem. Lett., 1999, 9, 1625. Thisamine intermediate is subjected to a reductive amination withdiethylphosphonoacetaldehyde (obtained from ozonolysis of diethylallyphosphonate) in the presence of a reducing agent such as sodiumtriacetoxyborohydride to generate the desired amine linker analog (J.Org. Chem., 1996, 61, 3849). Alternatively, the amine is acylated withan activated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960 and J. Med. Chem., 1984, 27, 600. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-pentanedioic acid (commerciallyavailable) is treated in a solvent such as acetonitrile withtriethylamine, 1-hydroxybenzotriazole, 4-methoxybenzylamine, and1,3-dicyclohexylcarbodiimide. After the reaction is complete, thesolvent is removed and the residue is purified by chromatography togenerate the desired analog, according to a procedure such as thatreported in J. Med. Chem., 2003, 46, 3793.

EXAMPLE 100 Preparation of Representative Compound of Formula 101

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 101 can be prepared asfollows.

Dexketoprofen is converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Dexketoprofen is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid is obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from dexketoprofen is converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of dexketoprofen, according to a procedure suchas that reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 101 Preparation of Representative Compound of Formula 102

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 102 can be preparedas follows.

Zardaverine can be treated in a solvent such as DMF or THF with a basesuch as sodium hydride. When bubbling ceases, E-1,4-dibromobutene isadded in excess. After quenching the reaction with aqueous ammoniumchloride and extracting the product with an organic solvent such asethyl acetate, the mono-alkylated product is isolated by chromatography.The allylic bromide is then heated with triethylphosphite in a solventsuch as toluene (or other Arbuzov reaction conditions: see Engel, R.,Synthesis of carbon-phosphorus bonds, CRC press, 1988) to generate thediethyl ester of the desired phosphonic acid.

EXAMPLE 102 Preparation of Representative Compounds of Formula 102

Other specific compounds of Formula 102 can be prepared as illustratedabove.

EXAMPLE 103 Preparation of Representative Compounds of Formula 103

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 103 can be prepared asfollows.

6-Methoxy-2-naphthylacetic acid, a major active metabolite of nabumetone(commercially available), can be converted to its acid chloride bytreatment with oxalyl chloride in dimethylformamide. The acid chlorideis then coupled with 2-aminoethylphosphonic acid diethyl ester in thepresence of a base such as triethylamine in a solvent such asdichloromethane to generate the desired amide product.

6-Methoxy-2-naphthylacetic acid can be treated in a solvent such asacetonitrile with diphenylphosphoryl azide in the presence of a basesuch as triethylamine at room temperature or up to reflux temperature.After cooling, the mixture is treated with diluted hydrochloric acid toprovide the amine (J. Org. Chem., 2002, 67, 6260). The amine is thenacylated with an activated diethylphosphonoacetic acid to provide thedesired amide linker compound, according to a procedure such as thosereported in J. Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984,27, 600-604. The activated diethylphosphonoacetic acid can be obtainedby treatment in a solvent such as dimethylformamide with a couplingreagent such as diethyl cyanophosphonate and a base such asdiisopropylethylamine at room temperature.

The amine derived from 6-methoxy-2-naphthylacetic acid can be convertedto the alcohol, according to a procedure such as that reported in J.Org. Chem., 1999, 64, 4159. Accordingly, the amine is dissolved in amixed solvent of acetic acid and water, to which sodium nitrite in wateris added dropwise to afford the desired alcohol. The alcohol is thenconverted to the bromide by treatment with triphenylphosphine andtetrabromomethane, according to a procedure such as that described in J.Org. Chem., 2002, 67, 7215. The bromide is treated in a solvent such astetrahydrofuran with sodium salt of phosphonic acid diethyl ester toprovide the desired phosphonate derivative of nabumetone, according to aprocedure such as that reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 104 Preparation of Representative Compounds of Formula 104

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 104 can be prepared asfollows.

Licofelone is converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Licofelone is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from licofelone can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of licofelone, according to a procedure such asthat reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 105 Preparation of Representative Compounds of Formula 105

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 105 can be prepared asfollows.

Ketorolac is converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Ketorolac is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from ketorolac can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of ketorolac, according to a procedure such asthat reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 106 Preparation of Representative Compounds of Formula 106

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 106 can be preparedas follows.

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound106.1, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOCanhydride as described in Greene, T., Protective groups in organicsynthesis, Wiley-Interscience, 1999. Compound 106.1 is then treated in asolvent such as tetrahydrofuran or dimethylformamide with a base such assodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added,yielding the desired phosphonate diester 106.2 after deprotection of theBOC group using trifluoroacetic acid (TFA).

EXAMPLE 107 Preparation of Representative Compounds of Formula 107

Representative compounds of the invention can be prepared as illustratedabove. Deprotected compound 107.1((1R)-1-(9-deazahypoxanthin-9-yl)-1,2,4-trideoxy-1,4-imino-D-erythro-pentitol,as the hydrochloride salt) is prepared as described in Evans, G. B. etal., Tetrahedron, 2000, 56, 3053, using di-t-butyl dicarbonate indichloromethane. Oxidation of the 5′-OH followed by elimination providesglycal 107.2 (see the procedure of Zemlicka J. et al., J. Am. Chem.Soc., 1972, 94, 9, 3213). Selenoetherification provides the protectedphosphonate 107.3 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642).Oxidative elimination of the phenylselenide (as described in Kim, C. etal., J. Org. Chem., 1991, 56, 2642) followed by stereoselectivedihydroxylation provides the desired diol 107.4. Finally, the protectinggroup is removed to provide compound 107.5.

A specific compound of Formula 107 can be prepared as follows.

Specifically,(1R)-1-(9-deazahypoxanthin-9-yl)-1,2,4-trideoxy-1,4-imino-D-erythro-pentitol,prepared as the HCl salt as described in Evans, G. B. et al.,Tetrahedron, 2000, 56, 3053, is first protected and then oxidized withPtO₂ to provide carboxylic acid 107.7. Decarboxylative elimination isachieved using dimethylformamide dineopentyl acetal in dimethylformamideat high temperature (Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9,3213). Selenoetherification followed by treatment of the protectedglycal with silver perchlorate in the presence ofdiethyl(hydroxylmethyl)phosphonate (Phillion, D. et al., TetrahedronLett., 1986, 27, 1477) provides the phosphonate 107.9 (Kim, C. et al.,J. Org. Chem., 1991, 56, 2642). Oxidative elimination of the selenidefollowed by dihydroxylation using osmium tetraoxide provides diol107.11. Removal of the amine protecting group, according to theprocedure of Greene, T., Protective groups in organic synthesis,Wiley-Interscience, 1999, provides compound 107.12.

EXAMPLE 108 Preparation of Representative Compounds of Formula 108

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 108 can be prepared asfollows.

Tolmetine, an active metabolite of amtolmetine guacil, is converted toits acid chloride by treatment with oxalyl chloride indimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Tolmetine is treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid is obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from tolmetine is converted to the alcohol accordingto the procedure reported in J. Org. Chem., 1999, 64, 4159. Accordingly,the amine is dissolved in a mixed solvent of acetic acid and water, towhich sodium nitrite in water is added dropwise to afford the desiredalcohol. The alcohol is then converted to the bromide by treatment withtriphenylphosphine and tetrabromomethane, according to a procedure suchas that described in J. Org. Chem., 2002, 67, 7215. The bromide istreated in a solvent such as tetrahydrofuran with sodium salt ofphosphonic acid diethyl ester to provide the desired phosphonatederivative of amtolmetine guacil, according to a procedure such as thatreported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 109 Preparation of Representative Compounds of Formula 109

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 109 can be prepared asfollows.

Diclofenac, a metabolite and a synthetic precursor of aceclofenac, canbe converted to its acid chloride by treatment with oxalyl chloride indimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired compound.

Diclofenac can be treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from diclofenac can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of aceclofenac, according to a procedure such asthat reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 110 Preparation of Representative Compounds of Formula 110

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 110 can be prepared asfollows.

Ibuprofen, an active metabolite of metoxibutropate, can be converted toits acid chloride by treatment with oxalyl chloride indimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Ibuprofen can be treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from ibuprofen can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of metoxibutropate, according to a procedure suchas that reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 111 Preparation of Representative Compounds of Formula 111

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula III can be prepared asfollows.

Oxaprozin can be converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Oxaprozin can be treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from oxaprozin can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of oxaprozin, according to a procedure such asthat reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 112 Preparation of Representative Compounds of Formula 112

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 112 can be prepared asfollows.

Sulindac can be converted to its acid chloride by treatment with oxalylchloride in dimethylformamide. The acid chloride is then coupled with2-aminoethylphosphonic acid diethyl ester in the presence of a base suchas triethylamine in a solvent such as dichloromethane to generate thedesired amide product.

Sulindac can be treated in a solvent such as acetonitrile withdiphenylphosphoryl azide in the presence of a base such as triethylamineat room temperature or up to reflux temperature. After cooling, themixture is treated with diluted hydrochloric acid to provide the amine(J. Org. Chem., 2002, 67, 6260). The amine is then acylated with anactivated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960-964 and J. Med. Chem., 1984, 27, 600-604. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

The amine derived from sulindac can be converted to the alcohol,according to a procedure such as that reported in J. Org. Chem., 1999,64, 4159. Accordingly, the amine is dissolved in a mixed solvent ofacetic acid and water, to which sodium nitrite in water is addeddropwise to afford the desired alcohol. The alcohol is then converted tothe bromide by treatment with triphenylphosphine and tetrabromomethane,according to a procedure such as that described in J. Org. Chem., 2002,67, 7215. The bromide is treated in a solvent such as tetrahydrofuranwith sodium salt of phosphonic acid diethyl ester to provide the desiredphosphonate derivative of sulindac, according to a procedure such asthat reported in Tetrahedron, 1996, 52, 4411.

EXAMPLE 113 Preparation of Representative Compounds of Formulae 113 and114

Representative compounds of the invention can be prepared as illustratedabove. For example, specific compounds of Formula 113 and 114 can beprepared as follows.

2-Methyl-4-nitrobenzoic acid methyl ester (commercially available) isconverted to3-(5-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione,following the procedures reported in Bioorg. Med. Chem. Lett., 1999, 9,1625. This amine intermediate is subjected to a reductive amination withdiethylphosphonoacetaldehyde (obtained from ozonolysis of diethylallyphosphonate) in the presence of a reducing agent such as sodiumtriacetoxyborohydride to generate the desired amine linker analog (J.Org. Chem., 1996, 61, 3849). Alternatively, the amine is acylated withan activated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960 and J. Med. Chem., 1984, 27, 600. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

2-Methyl-3-nitrobenzoic acid methyl ester (commercially available) istreated in a solvent such as carbon tetrachloride withN-bromosuccinimide under light to produce 2-bromomethyl-3-nitrobenzoicacid methyl ester. This benzylic bromide is treated in a solvent such asdimethylformamide with[2-(3-amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonic acid diethylester (for the preparation of this compound, see below) in the presenceof a base such as triethylamine. The coupled product is then reduced byhydrogenation (Bioorg. Med. Chem. Lett., 1999, 9, 1625) to afford thedesired analog.

[2-(3-Amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonic acid diethylester is obtained according to a procedure such as that reported in J.Med. Chem., 2003, 46, 3793. Accordingly, benzyloxycarbonyl-protectedglutaric acid is treated in a solvent such as acetonitrile withtriethylamine, 1-hydroxy-benzotriazole, diethyl 2-aminoethyl-phosphonateand 1,3-dicyclohexyl-carbodiimide. After the reaction is complete, thesolvent is removed and the residue is purified by chromatography togenerate the cyclic product, which is subjected to hydrogen in thepresence of palladium catalysis to afford the desired intermediate.

EXAMPLES 114-117 Diproline Derivatives

The structures of Diprolene (German Patent DE 2905674) andrepresentative diproline phosphonate derivatives of the invention areshown below, in which the substituent R¹ is H, alkyl, alkenyl, aryl oraralkyl. The derivatives incorporate a phosphonate moiety (R¹O)₂P(O)connected to the nucleus by means of a variable linking group,designated as “link” in the attached structures.

The synthesis of representative phosphonate derivatives of diproline isoutlined in Examples 114-117. In these Examples, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 114 Preparation of Representative Diproline Derivatives

The steroid side-chain is protected as a bis-methylenedioxy (BMD)moiety. In this sequence, the propionate esters are hydrolyzed, forexample by reaction with two molar equivalents of lithium hydroxide inaqueous dimethoxyethane solution at ambient temperature, to give thediol 114.2. The product is then reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in ProtectiveGroups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative 114.3. Thephosphonate moiety is then introduced, using the procedures describedbelow, to produce the phosphonate ester 114.4. Prior to hydrolysis ofthe BMD protecting group, the 11-hydroxyl group is protected. Theprotecting group is selected so that it is stable to the conditionsrequired for removal of the BMD group, and so that it is removablewithout affecting the subsequently introduced 17, 21-diester moiety. Forexample, the 11-hydroxyl group is protected by conversion to the4-azidobutyrate ester, by reaction with 4-azidobutyryl chloride inpyridine. The 11-azidobutyrate group is then removed from the diester114.7 by reaction with triphenylphosphine, as described in Bull. Soc.Chem. Jpn., 59, 1296, 1986. Alternatively, the 11-hydroxyl group isprotected by conversion to the 2-(trimethylsilyl)ethyl carbonate, byreaction with 2-(trimethylsilyl)ethyl carbonyl chloride and pyridine.The 2-(trimethylsilyl) carbonate is removed from the diester 114.7 byreaction with tetrabutylammonium fluoride in tetrahydrofuran at ambienttemperature, as described in Tet. Lett., 22, 969, 1981.

Alternatively, the 11-hydroxyl group is protected by conversion to thetrichloroacetyl ester, by reaction with trichloroacetyl chloride indimethylformamide-pyridine. The trichloroacetyl ester is removed byreaction with ethanolic ammonia at ambient temperature, as described inColl. Czech. Chem. Commun., 27, 2567, 1962.

The BMD moiety in the protected product 114.5 is then hydrolyzed, forexample by treatment with 50% aqueous acetic acid, as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the diol 114.6; thelatter compound is then acylated, for example by reaction with propionicacid and dicyclohexyl carbodiimide in dimethylformamide at ambienttemperature, or by reaction with propionyl chloride and triethylamine indichloromethane, to produce the dipropionate 114.7. Deprotection of the11-hydroxyl group, as described above, then affords the diester 114.8.

Alternatively, the 20-ketone group is protected as the diethylamineadduct by reaction with titanium tetrakis(diethylamide), as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. MWuts, Wiley, Second Edition 1990, p. 219.

EXAMPLE 115 Preparation of Representative Diproline Derivatives

The preparation of phosphonate derivatives of diproline in which thephosphonate is attached by means of an imino or iminoxy group and avariable carbon chain is illustrated above. In this procedure, theBMD-protected derivative 114.3 is reacted with an amine or hydroxylamine115.1, in which R² is an alkyl, alkenyl, cycloalkyl or cycloalkenylgroup, optionally incorporating a heteroatom O, S or N, or a functionalgroup such as an amide, ester, oxime, sulfoxide or sulfone etc, or anoptionally substituted aryl, heteroaryl or aralkyl group, optionallyincorporating a heteroatom O, S or N, to afford the imine or iminoxyproduct 115.2. The reaction is conducted between equimolar amounts ofthe reactants in an aprotic solvent such as pyridine or xylene, or in analcoholic solvent such as ethanol, optionally in the presence of an acidcatalyst, to give the imine or oxime. The preparation of oximes ofsteroidal 3-ketones is described in Anal. Bioch., 1978, 86, 133. and inJ. Mass. Spectrom., 1995, 30, 497. The BMD-protected compound 115.2 isthen converted, as described in example 114 into the diester 115.3.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 115.4,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 115.5(Aldrich) to produce the ether 115.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine, to give the product 115.6.Deprotection, for example by treatment with trifluoroacetic acid, thengives the hydroxylamine ether 115.7.

The preparation of phosphonate derivatives of diproline in which thephosphonate is attached by means of an iminoxy group is illustratedabove. In this procedure, the substrate 114.3 is reacted with a dialkylphosphonomethyl hydroxylamine 115.8, prepared as described above from adialkyl trifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford, after deprotection and sidechain acylation, the oxime ether 115.9. The oxime forming reaction isperformed at ambient temperature in pyridine solution between equimolaramounts of the reactants. Using the above procedures, but employing, inplace of the oxime ether 115.8, different oxime ethers 115.7, thecorresponding products 115.3 are obtained.

The preparation of phosphonate derivatives of diproline incorporating animinoxy group, by means of the reaction between the substrate 114.3 andO-2-(5-bromo-2-thienyl)ethoxyhydroxylamine 115.10, prepared as describedabove from 2-(5-bromo-2-thienyl)ethyl bromide (J. Chem. Soc., PerkinTrans. Phys. Org. Chem., 1975, 821) is illustrated above. The resultantoxime ether is converted, by deprotection and side chain acylation, intothe compound 115.11 which is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite 115.12 to afford thephosphonate 115.13. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 35, 1371, 1992. The reaction is performed inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo-substituted product 115.11 is coupled, in apalladium-catalyzed Heck reaction, with a dialkyl propenyl phosphonate115.14 (Acros) to give the unsaturated phosphonate 115.15. The couplingof aryl halides with olefins by means of the Heck reaction is described,for example, in Advanced Organic Chemistry, by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12, 146, 1979.The aryl bromide and the olefin are coupled in a polar solvent such asdimethylformamide or dioxan, in the presence of a palladium(0) catalystsuch as tetrakis(triphenylphosphine)palladium(0) or palladium(II)catalyst such as palladium(II) acetate, and optionally in the presenceof a base such as triethylamine or potassium carbonate. Optionally, thestyrenoid double bond present in the product 115.15 is reduced, forexample by reaction with diimide, to produce the saturated analog115.16. The reduction of olefinic bonds is described in ComprehensiveOrganic Transformations, by R. C. Larock, VCH, 1989, p. 6ff. Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromothienylreagent 115.10, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 115.13, 115.15 and 115.16 areobtained.

The preparation of phosphonate derivatives of diproline in which thephosphonate is attached by means of an imino group is illyustratedabove. In this procedure, the substrate 114.3 is reacted with a dialkyl2-aminophenyl phosphonate 115.17 (Aurora) to give, after deprotectionand side chain acylation, the imine product 115.18. The reaction isconducted in a hydrocarbon solvent such as toluene or xylene, at refluxtemperature, in the presence of a basic catalyst such as sodiummethoxide, or an acid catalyst such as p-toluenesulfonic acid, underazeotropic conditions, to give the product 115.18.

Using the above procedures, but employing, in place of the 2-aminophenylphosphonate 115.17, different amino-substituted aryl or heteroarylphosphonates, products analogous to 115.18 are obtained.

An alternative method for the preparation of phosphonate derivatives inwhich the phosphonate is attached by means of an oximino group isillustrated above. In this procedure, the dienone 114.3 is reacted withO-(carboxymethyl)hydroxylamine 115.19 (Interchim) to yield, afterdeprotection and side chain acylation, the oxime 115.19. The reaction ofsteroidal 1,4-dien-3-ones with hydroxylamine is described in J. SteroidBioch., 1976, 7, 795. The reaction is performed between equimolaramounts of the reactants in a polar organic solvent such as pyridine ormethanol, optionally in the presence of acetic acid or sodium acetate.The oxime 115.20 is then reacted with a dialkyl 3-hydroxyphenylphosphonate 115.21 (Epsilon) in a Mitsonobu reaction, to yield thesubstituted oxime 115.22. The preparation of aromatic ethers andthioethers by means of the Mitsonobu reaction is described, for example,in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.448, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335. Thephenol and the hydroxy or mercapto component are reacted together in anaprotic solvent such as, for example, tetrahydrofuran, in the presenceof a dialkyl azodicarboxylate and a triarylphosphine, to afford theether or thioether products. The procedure is also described in Org.React., 1992, 42, 335-656. The product 115.22 is then transformed, bydeprotection and acylation, into the diester 115.23.

Using the above procedures, but employing, in place of the phosphonate115.22 different dialkyl hydroxy-substituted aryl or heteroarylphosphonates, the products analogous to 115.23 are obtained.

EXAMPLE 116 Preparation of Representative Diproline Derivatives

The preparation of phosphonate esters of diproline in which thephosphonate group is attached to the 1′ or 2′ position of the pyrazolering, by means of an aromatic or heteroaromatic group, a heteroatom anda variable carbon chain is illustrated above. In this procedure,Diprolene 116.1 is reduced to afford the 1,2-dihydro product, 116.2. Thecatalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in Australian PatentApplication 275950409, to afford the 2-formyl product 116.3. Optionally,the substrate 116.1 is protected, for example as described in example114, prior to the formylation reaction, as described in J. Am. Chem.Soc., 1964, 86, 1520. The 2-formyl product is then reacted with an arylor heteroaryl hydrazine 116.4, in which the substituent X is either aphosphonate group or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields theisomeric 2′- and 1′-aryl pyrazoles 116.5 and 116.6. The ring-formingreaction is performed between equimolar amounts of the reactants in anacidic solvent such as acetic acid, as described in J. Am. Chem. Soc.,1964, 86, 1520. The pyrazoles 116.5 and 116.6 are then transformed,respectively into the phosphonates 116.7 and 116.8.

The preparation of phosphonate derivatives of diproline in which thephosphonate is attached by means of a phenyl group is illustrated above.In this sequence, the ketoaldehyde 116.3 is reacted, as described above,with 2-bromophenylhydrazine 116.9 (Fluka), to give the isomeric pyrazoleproducts 116.10 and 16.11. The products are then reacted, as describedabove, with a dialkyl phosphite HP(O)(OR¹)₂ and a palladium catalyst, toafford respectively the phosphonates 116.12 and 116.13. Using the aboveprocedures, but employing, in place of 2-bromophenyl hydrazine,different bromoaryl or bromoheteroaryl hydrazines 116.4, the products116.7 and 116.8 are obtained.

The preparation of phosphonate diproline derivatives in which thephosphonate is attached by means of an aromatic or heteroaromatic groupand a saturated or unsaturated alkyl chain is illustrated above. In thisprocedure, the bromophenyl-substituted pyrazole 116.10 is coupled in aHeck reaction, as described above, with, for example a dialkyl butenylphosphonate 116.14 (Org. Lett., 2001, 3, 217) to give the unsaturatedphosphonate product 116.15. Optionally, the product is reduced, asdescribed above, to give the saturated analog 116.16. Application of theabove procedures to the isomeric bromophenyl pyrazole 116.11 affords theproducts isomeric with 116.15 and 116.16. Using the above procedures,but employing, in place of the phosphonate 116.14, different dialkylalkenyl phosphonates, and/or different bromoaryl or heteroaryl pyrazoles116.5 or 116.6, the products analogous to 116.15 and 116.16 areobtained.

The preparation of phosphonate diproline deravitives in which thephosphonate is attached by means of an aryl or heteroaryl group and analkoxy chain is illustrated above. In this procedure, 4-aminothiophenol116.17 is reacted in dimethylformamide solution at ambient temperaturewith a dialkyl trifluoromethanesulfonyloxymethyl phosphonate 116.18(Tet. Lett., 1986, 27, 1477) and potassium carbonate to give thethioether 116.19. The product is then converted into the correspondinghydrazine 116.20 by means of a diazotization reaction in aqueousethanolic hydrochloric acid, followed by reduction of the diazoniumchloride with tin(II) chloride, as described in J. Med. Chem., 2001, 44,4031. The hydrazine is then reacted, as described above, with theketoaldehyde 116.3, to form the isomeric pyrazoles 116.21 and 116.22.

Using the above procedures, but employing, in place of the triflate116.18, different dialkylphosphono alkyl bromides or triflates, and/ordifferent aromatic or heteroaromatic mercapto or hydroxyamines, theproducts analogous to 116.21 and 116.22 are obtained.

The preparation of phosphonate diprolone derivatives in which thephosphonate is attached by means of a pyridyl group a heteroatom and avariable carbon chain is illustrated above. In this procedure,3-amino-5-hydroxypyridine is converted, by reaction with aceticanhydride, into the diacetyl analog 116.24. The product is thentransformed by diazotization and reduction, as described above, into thehydrazine 116.25. The hydrazine is then reacted with the ketoaldehyde116.3 to give the isomeric pyrazoles 116.26 and 116.27. The 2′-pyridylproduct 116.26 is reacted in a Mitsonobu reaction, as described above,with a dialkyl hydroxyethyl phosphonate 116.28 (Zh. Obschei. Khim.,1973,43, 2364) to afford the ether 116.29. Application of this procedureto the isomeric phenol 116.27 affords the product isomeric to 116.29.

Alternatively, the isomeric phenol 116.27 is reacted, indimethylformamide solution at about 800, with one molar equivalent of adialkyl bromopropynyl phosphonate 116.30 (Bioorg. Med. Chem. Lett.,1994,4, 273) and cesium carbonate, to prepare the phosphonate 116.31.Application of this procedure to the isomeric phenol 116.26 affords theproduct isomeric with 116.31. Using the above procedures, but employing,in place of the carbinol 116.28 or the bromide 116.30, different thiols,alcohols or bromides, and/or different phenols 116.5 or 116.6 in which Xis OH, the corresponding products analogous to 116.29 and 116.31 areobtained.

EXAMPLE 117 Preparation of Representative Diproline Derivatives

The preparation of the phosphonate diproline derivatives in which thephosphonate group is attached by means of a variable carbon linkage isillustrated above. In this procedure, the ketoaldehyde 116.3 is reactedwith hydrazine, to afford the pyrazole derivative 117.1. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The resulting pyrazole is then reacted with a dialkylbromomethyl phosphonate 117.2, in which R² is as defined above, toproduce the isomeric 2′ and 1′ alkylation products 117.3 and 117.4respectively. The alkylation of substituted pyrazoles is described, forexample, in Heterocyclic Chemistry, by T. L. Gilchrist, Longman, 1992,p. 309.

Representative diproline derivatives of the invention can be prepared asillustrated above. The pyrazole 117.1 is reacted, in dimethylformamidesolution at ca. 90°, with a dialkyl bromopropyl phosphonate 117.5(Aldrich) and a base such as dimethylaminopyridine or lithiumhexamethyldisilazide, to yield the isomeric alkylation products 117.6and 117.7.

Representative diproline derivatives of the invention can be prepared asillustrated above. The pyrazole 117.1 is reacted in dimethylformamidesolution at ambient temperature with one molar equivalent of1,4-dibromobut-2-yne 117.8 (Narchem) and potassium carbonate, to affordthe alkylation products 117.9 and 117.10. The products are then heatedat 120° with a trialkyl phosphite in an Arbuzov reaction, to yield thephosphonates 117.11 and 117.12. The Arbuzov reaction is described inHandb. Organophosphorus Chem., 1992, 115-72. Using the above procedures,but employing, in place of the dibromide 117.8, different alkyl, alkenylor alkynyl dibromides, the products analogous to 117.11 and 117.12 areobtained.

EXAMPLES 118-121 Aclometazone Derivatives (118-120)

The structures of Aclometasone dipropionate (J. Med. Chem., 1980, 23,430; U.S. Pat. No. 4,124,707) and representative phosphonate esters ofthe invention are shown below, in which the substituent R¹ is H, alkyl,alkenyl, aryl or aralkyl. These compounds incorporate a phosphonatemoiety (R¹O)₂P(O) connected to the nucleus by means of a variablelinking group, designated as “link” in the attached structures.

The synthesis of representative phosphonate derivatives of the inventionis outlined in Examples 118-121. In these Examples, it may be necessaryto protect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 118 Preparation of Representative Aclometasone Derivatives

As illustrated above, a protection-deprotection sequence in which thesteroid side-chain is protected as a bis-methylenedioxy (BMD) moiety. Inthis sequence, the propionate esters are hydrolyzed, for example byreaction with two molar equivalents of lithium hydroxide in aqueousdimethoxyethane solution at ambient temperature, to give the diol 118.2.The product is then reacted with paraformaldehyde and an acid catalystsuch as hydrochloric acid, as described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition1990, p. 223, to yield the BMD derivative 118.3. The phosphonate moietyis then introduced, using the procedures described below, to produce thephosphonate ester 118.4. Prior to hydrolysis of the BMD protectinggroup, the 11-hydroxyl group is protected. The protecting group isselected so that it is stable to the conditions required for removal ofthe BMD group, and so that it is removable without affecting thesubsequently introduced 17, 21-diester moiety. For example, the11-hydroxyl group is protected by conversion to the 4-azidobutyrateester, by reaction with 4-azidobutyryl chloride in pyridine. The11-azidobutyrate group is then removed from the diester 118.7 byreaction with triphenylphosphine, as described in Bull. Soc. Chem. Jpn.,59, 1296, 1986. Alternatively, the 1-hydroxyl group is protected byconversion to the 2-(trimethylsilyl)ethyl carbonate, by reaction with2-(trimethylsilyl)ethyl carbonyl chloride and pyridine. The2-(trimethylsilyl) carbonate is removed from the diester 118.7 byreaction with tetrabutylammonium fluoride in tetrahydrofuran at ambienttemperature, as described in Tet. Lett., 22, 969, 1981.

Alternatively, the 11-hydroxyl group is protected by conversion to thetrichloroacetyl ester, by reaction with trichloroacetyl chloride indimethylformamide-pyridine. The trichloroacetyl ester is removed byreaction with ethanolic ammonia at ambient temperature, as described inColl. Czech. Chem. Commun., 27, 2567, 1962.

The BMD moiety in the protected product 118.5 is then hydrolyzed, forexample by treatment with 50% aqueous acetic acid, as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the diol 118.6; thelatter compound is then acylated, for example by reaction with propionicacid and dicyclohexyl carbodiimide in dimethylformamide at ambienttemperature, or by reaction with propionyl chloride and triethylamine indichloromethane, to produce the dipropionate 118.7. Deprotection of the11-hydroxyl group, as described above, then affords the diester 118.8.

Alternatively, the 20-ketone group is protected as the diethylamineadduct by reaction with titanium tetrakis(diethylamide), as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. MWuts, Wiley, Second Edition 1990, p. 219.

EXAMPLE 119 Preparation of Representative Aclometasone Derivatives

The preparation of phosphonate derivatives of Aclometasone in which thephosphonate is attached by means of an imino or iminoxy group and avariable carbon chain is illustrated above. In this procedure, theBMD-protected derivative 118.3 is reacted with an amine or hydroxylamine119.1, in which R² is an alkyl, alkenyl, cycloalkyl or cycloalkenylgroup, optionally incorporating a heteroatom O, S or N, or a functionalgroup such as an amide, ester, oxime, sulfoxide or sulfone etc, or anoptionally substituted aryl, heteroaryl or aralkyl group, optionallyincorporating a heteroatom O, S or N, to afford the imine or iminoxyproduct 119.2. The reaction is conducted between equimolar amounts ofthe reactants in an aprotic solvent such as pyridine or xylene, or in analcoholic solvent such as ethanol, optionally in the presence of an acidcatalyst to give the imine or oxime. The preparation of oximes ofsteroidal 3-ketones is described in Anal. Bioch., 1978, 86, 133. and inJ. Mass. Spectrom., 1995, 30, 497. The BMD-protected side-chain compound119.2 is then converted, as described in Example 118 into the diester119.3.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 119.4,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 119.5(Aldrich) to produce the ether 119.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine, to give the product 119.6.Deprotection, for example by treatment with trifluoroacetic acid, thengives the hydroxylamine ether 119.7.

The preparation of phosphonate aclometasone derivatives in which thephosphonate is attached by means of an iminoxy group is shown above. Inthis procedure, the substrate 118.3 is reacted with a dialkylphosphonomethyl hydroxylamine 119.8, prepared as described above from adialkyl trifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford, after deprotection and sidechain acylation, the oxime ether 119.9. The oxime forming reaction isperformed at ambient temperature in pyridine solution between equimolaramounts of the reactants. Using the above procedures, but employing, inplace of the oxime ether 119.8, different oxime ethers 119.7, thecorresponding products 119.3 are obtained.

The preparation of phosphonate aclometasone derivatives incorporating animinoxy group, by means of the reaction between the substrate 118.3 andO-2-(3-bromophenyl)ethoxyhydroxylamine 119.10, prepared as describedabove from 2-(3-bromophenyl)ethyl bromide is illustrated above. Theresultant oxime ether is converted, by deprotection and side chainacylation, into the compound 119.11 which is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphite 119.12 toafford the phosphonate 119.13. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem., 35, 1371, 1992. The reactionis performed in an inert solvent such as toluene, in the presence of abase such as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo-substituted product 119.11 is coupled, in apalladium-catalyzed Heck reaction, with a dialkyl vinyl phosphonate119.14 (Aldrich) to give the unsaturated phosphonate 119.15. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12,146, 1979. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or a palladium(II) catalyst such as palladium(II) acetate, andoptionally in the presence of a base such as triethylamine or potassiumcarbonate. Optionally, the styrenoid double bond present in the product119.15 is reduced, for example by reaction with diimide, to produce thesaturated analog 119.16. The reduction of olefinic bonds is described inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromophenylreagent 119.10, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 119.13, 119.15 and 119.16 areobtained.

The preparation of phosphonate aclometasone derivatives in which thephosphonate is attached by means of an imino group is illustrated above.In this procedure, the substrate 118.3 is reacted with a dialkyl3-aminophenyl phosphonate 119.17 (J. Med. Chem., 1984, 27, 654) to give,after deprotection and side chain acylation, the imine product 119.18.The reaction is conducted in a hydrocarbon solvent such as toluene orxylene, at reflux temperature, in the presence of a basic catalyst suchas sodium methoxide, or an acid catalyst such as p-toluenesulfonic acid,under azeotropic conditions, to give the product 119.18. Using the aboveprocedures, but employing, in place of the 3-aminophenyl phosphonate119.17, different amino-substituted aryl or heteroaryl phosphonates,products analogous to 119.18 are obtained.

An alternative method for the preparation of phosphonate aclometasonederivatives in which the phosphonate is attached by means of an oximinogroup is illustrated above. In this procedure, the dienone 118.3 isreacted with hydroxylamine to yield, after deprotection and side chainacylation, the oxime 119.19. The reaction of steroidal 1,4-dien-3-oneswith hydroxylamine is described in J. Steroid Bioch., 1976, 7, 795; thereaction is performed between equimolar amounts of the reactants in apolar organic solvent such as pyridine or methanol, optionally in thepresence of acetic acid or sodium acetate. The oxime is then reactedwith a dialkyl 3-hydroxyphenyl phosphonate 119.20 (Epsilon) in aMitsonobu reaction, to yield the substituted oxime 119.21. Thepreparation of aromatic ethers and thioethers by means of the Mitsonobureaction is described, for example, in Comprehensive OrganicTransformations, by R. C. Larock, VCH, 1989, p. 448, and in AdvancedOrganic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum,2001, p. 153-4 and in Org. React., 1992, 42, 335. The phenol and thehydroxy or mercapto component are reacted together in an aprotic solventsuch as, for example, tetrahydrofuran, in the presence of a dialkylazodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656.

Using the above procedures, but employing, in place of the phosphonate119.20, different dialkyl hydroxy-substituted aryl or heteroarylphosphonates, the products analogous to 119.21 are obtained.

EXAMPLE 120 Preparation of Representative Aclometasone Derivatives

The preparation of the phosphonate aclometasone derivatives in which thephosphonate group is attached to the 1′ or 2′ position of the pyrazolering, by means of an aromatic or heteroaromatic group, a heteroatom anda variable carbon chain is illustrated above. In this procedure,Aclometasone dipropionate 120.1 is reduced to afford the 1,2-dihydroproduct, 120.2. The catalytic hydrogenation reaction is effected by theuse of tris(triphenylphosphine)rhodium (I) chloride, for example asdescribed in J. Med. Chem., 2001, 44, 602. The product is then reactedwith ethyl formate and a base such as sodium hydride, in an inertsolvent such as toluene or dimethylformamide, as described in AustralianPatent Application 275950409, to afford the 2-formyl product 120.3.Optionally, the substrate 120.1 is protected prior to the formylationreaction, as described in J. Am. Chem. Soc., 1964, 86, 1520. The2-formyl product is then reacted with an aryl or heteroaryl hydrazine120.4, in which the substituent X is either a phosphonate group or agroup which is subsequently transformed into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxyl and the like. The reaction yields the isomeric 2′- and 1-arylpyrazoles 120.5 and 120.6. The ring-forming reaction is performedbetween equimolar amounts of the reactants in an acidic solvent such asacetic acid, as described in J. Am. Chem. Soc., 1964, 86, 1520. Thepyrazoles 120.5 and 120.6 are then transformed, respectively, into thephosphonates 120.7 and 120.8.

The preparation of phosphonate aclometasone derivatives in which thephosphonate is attached by means of a phenyl group is illustrated above.In this sequence, the ketoaldehyde 120.3 is reacted, as described above,with 3-bromophenylhydrazine 120.9 (Fluka), to give the isomeric pyrazoleproducts 120.10 and 120.11. The products are then reacted, as describedabove, with a dialkyl phosphite HP(O)(^(OR) ¹)₂ and a palladiumcatalyst, to afford respectively the phosphonates 120.12 and 120.13.

Using the above procedures, but employing, in place of 3-bromophenylhydrazine, different bromoaryl or bromoheteroaryl hydrazines 12.4, thecorresponding products 120.7 and 120.8 are obtained.

The preparation of phosphonate aclometasone derivatives in which thephosphonate is attached by means of an aromatic or heteroaromatic groupand a saturated or unsaturated alkyl chain is illustrated above. In thisprocedure, the bromophenyl-substituted pyrazole 120.10 is coupled in aHeck reaction, as described above, with, for example a dialkyl vinylphosphonate 120.14 (Aldrich) to give the unsaturated phosphonate product120.15. Optionally, the product is reduced, as described above, to givethe saturated analog 120.16. Application of the above procedures to theisomeric bromophenyl pyrazole 120.11 affords the products isomeric with120.15 and 120.16.

Using the above procedures, but employing, in place of the phosphonate120.14, different dialkyl alkenyl phosphonates, and/or differentbromoaryl or heteroaryl pyrazoles 120.5 or 120.6 (X=Br) the productsanalogous to 120.15 and 120.16 are obtained.

The preparation of phosphonate aclometasone derivatives in which thephosphonate is attached by means of an aryl or heteroaryl group and analkoxy chain is illustrated above. In this procedure, 4-aminophenol120.17 is reacted in dimethylformamide solution at ambient temperaturewith a dialkyl trifluoromethanesulfonyloxymethyl phosphonate 120.18(Tet. Lett., 1986, 27, 1477) and potassium carbonate to give the ether120.19. The product is then converted into the corresponding hydrazine120.20 by means of a diazotization reaction in aqueous ethanolichydrochloric acid, followed by reduction of the diazonium chloride withtin(II) chloride, as described in J. Med. Chem., 2001, 44, 4031. Thehydrazine is then reacted, as described above, with the ketoaldehyde120.3, to form the isomeric pyrazoles 120.21 and 120.22.

Using the above procedures, but employing, in place of the triflate120.18, different dialkylphosphono alkyl bromides or triflates, and/ordifferent aromatic or heteroaromatic hydroxyamines, the productsanalogous to 120.21 and 120.22 are obtained.

The preparation of phosphonate aclometasone derivatives in which thephosphonate is attached by means of a pyridyl group a heteroatom and avariable carbon chain is illustrated above. In this procedure,3-amino-5-hydroxypyridine is converted, by reaction with aceticanhydride, into the diacetyl analog 120.24. The product is thentransformed by diazotization and reduction, as described above, into thehydrazine 120.25. The hydrazine is then reacted with the ketoaldehyde120.3 to give the isomeric pyrazoles 120.26 and 120.27. The 2′-pyridylproduct 120.26 is reacted in a Mitsonobu reaction, as described above,with a dialkyl mercaptoethyl phosphonate 120.28 (Zh. Obschei. Khim.,1973, 43, 2364) to afford the thioether 120.29. Application of thisprocedure to the isomeric phenol 120.27 affords the product isomeric to120.29.

Alternatively, the isomeric phenol 120.27 is reacted, indimethylformamide solution at ca. 800, with one molar equivalent of adialkyl bromobutenyl phosphonate 120.30 (J. Med. Chem., 1992, 35, 1371)and cesium carbonate, to prepare the phosphonate 120.31. Application ofthis procedure to the isomeric phenol 120.26 affords the productisomeric with 120.31.

Using the above procedures, but employing, in place of the thiol 120.28or the bromide 120.30, different thiols, alcohols or bromides, and/ordifferent phenols 120.5 or 120.6 in which X is OH, the correspondingproducts analogous to 120.29 and 120.31 are obtained.

EXAMPLE 121 Preparation of Representative Aclometasone Derivatives

The preparation of representative compounds of the invention in whichthe phosphonate group is attached by means of a variable carbon linkageis illustrated above. In this procedure, the ketoaldehyde 120.3 isreacted with hydrazine, to afford the pyrazole derivative 121.1. Thereaction of steroidal 2-formyl-3-ketones with hydrazine is described inJ. Am. Chem. Soc, 1964, 86, 1520. The reaction is performed in aceticacid at ambient temperature. The resulting pyrazole is then reacted witha dialkyl bromomethyl phosphonate 121.2, in which R² is as definedabove, to produce the isomeric 2′ and 1′ alkylation products 121.3 and121.4 respectively. The alkylation of substituted pyrazoles isdescribed, for example, in Heterocyclic Chemistry, by T. L. Gilchrist,Longman, 1992, p. 309.

The preparation of representative compounds of the invention isillustrated above. The pyrazole 121.1 is reacted, in dimethylformamidesolution at ca. 90°, with a dialkyl bromopropyl phosphonate 121.5(Aldrich) and a base such as dimethylaminopyridine or lithiumhexamethyldisilazide, to yield the isomeric alkylation products 121.6and 121.7.

The preparation of representative compounds of the invention isillustrated above. The pyrazole 121.1 is reacted, as described above,with a dialkyl 4-bromomethyl benzyl phosphonate 121.8 (Tet. 1998, 54,9341) to give the products 121.9 and 121.10.

EXAMPLES 122-125 Hydrocortisone Derivatives

The structures of hydrocortisone and representative phosphonate estersof the invention are shown below, in which the substituent R¹ is H,alkyl, alkenyl, aryl or aralkyl. These compounds incorporate aphosphonate moiety (R¹O)₂P(O) connected to the nucleus by means of avariable linking group, designated as “link” in the attached structures.

The synthesis of representative phosphonate derivatives ofhydrocortisone is outlined in Examples 122-125. In these Examples, itmay be necessary to protect certain reactive substituents from unwantedreactions by protection before the sequence described, and to deprotectthe substituents afterwards, according to the knowledge of one skilledin the art. Protection and deprotection of functional groups aredescribed, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990. The protectionand deprotection of steroidal ketones and alcohols is described inOrganic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J. A.Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactive substituentswhich may be protected are shown in the accompanying schemes as, forexample, [OH], [O], etc.

EXAMPLE 122 Preparation of Representative Hydrocortisone Derivatives

As illustrated above, the steroid side-chain is protected as abis-methylenedioxy (BMD) moiety. In this sequence, hydrocortisone 122.1is reacted with paraformaldehyde and an acid catalyst such ashydrochloric acid, as described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition1990, p. 223, to yield the BMD derivative 122.2. The phosphonate moietyis then introduced, using the procedures described below, to produce thephosphonate ester 122.3. The BMD moiety is then hydrolyzed, for exampleby treatment with 50% aqueous acetic acid, as described in ProtectiveGroups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to afford the triol 122.4

EXAMPLE 123 Preparation of Representative Hydrocortisone Derivatives

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate is attached by means of an imino or iminoxy group and avariable carbon chain is illustrated above. In this procedure, theBMD-protected derivative 122.2 is reacted with an amine or hydroxylamine123.1, in which R² is an alkyl, alkenyl, cycloalkyl or cycloalkenylgroup, optionally incorporating a heteroatom O, S or N, or a functionalgroup such as an amide, ester, oxime, sulfoxide or sulfone etc, or anoptionally substituted aryl, heteroaryl or aralkyl group, optionallyincorporating a heteroatom O, S or N, and X is either a phosphonategroup or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime 123.2. The preparation of oximes of steroidal 3-ketones isdescribed in Anal. Bioch., 1978, 86, 133. and in J. Mass. Spectrom.,1995, 30, 497. In cases in which X is not dialkylphosphono, thesubstituent X is converted, using the methods described below; into aphosphonate-containing substituent; the BMD-protected side-chain is thenremoved to afford the triol 123.3.

The preparation of intermediate hydroxylamine ethers incorporating aphosphonate group is illustrated above. In this procedure, a phosphonate123.4, in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 123.5(Aldrich) to produce the ether 123.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 123.7.

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate is attached by means of an iminoxy group is illustratedabove. In this procedure, the substrate 122.2 is reacted with a dialkylphosphonomethyl hydroxylamine 123.8, prepared as described above from adialkyl trifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford the oxime 123.9 which isdeprotected to afford the triol 123.10. The oxime forming reaction istypically performed at ambient temperature in ethanol-acetic acidsolution between equimolar amounts of the reactants. Using the aboveprocedures, but employing, in place of the hydroxylamine ether 123.8,different oxime ethers 123.7, the corresponding products 123.3 areobtained.

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate group is attached by means of a phenyl ethoxy group isillustrated above. In this procedure, the enone 122.2 is reacted, asdescribed above, with O-(3-bromophenyl)ethyl hydroxylamine 123.11,prepared as described above from 2-(3-bromophenyl)ethyl bromide (FrenchPatent FR 1481052), to give, after deprotection of the side-chain, theoxime 123.12. The product is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite 123.13 to afford thephosphonate 123.14. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 35, 1371, 1992. The reaction is performed inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 123.12 is coupled with a dialkylvinylphosphonate 123.15 (Aldrich) to afford the phosphonate 123.16. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12,146, 1979. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 123.16 isreduced, for example by reaction with diimide, to produce the saturatedanalog 123.17. The reduction of olefinic bonds is described inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromophenylethoxy reagent 123.11, different bromo-substituted aryl or heteroarylalkoxy hydroxylamines, and/or different dialkyl alkenyl phosphonates,the products analogous to the compounds 123.14, 123.16 and 123.17 areobtained.

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate is attached by means of an oximino group and an amidelinkage is illustrated above. In this procedure, the enone 122.2 isreacted with O-(2-aminoethyl)hydroxylamine 123.20 (Pol. J. Chem., 1981,55, 1163) to yield the oxime 123.21. The reaction of steroidal1,4-dien-3-ones with substituted hydroxylamines is described in J.Steroid Bioch., 1976, 7, 795. The reaction is performed betweenequimolar amounts of the reactants in a polar organic solvent such aspyridine or methanol, optionally in the presence of acetic acid orsodium acetate. The oxime is then coupled with a dialkyl 4-carboxyphenylphosphonate 123.22 (Epsilon), to yield the amide oxime 123.23. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in Organic Functional Group Preparations, by S.R. Sandler and W. Karo, Academic Press, 1968, p. 274, and ComprehensiveOrganic Transformations, by R. C. Larock, VCH, 1989, p. 972ff. Thecarboxylic acid is reacted with the amine in the presence of anactivating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid is first converted into an activatedderivative such as the acid chloride, anhydride, mixed anhydride,imidazolide and the like, and then reacted with the amine, in thepresence of an organic base such as, for example, pyridine, to affordthe amide. The conversion of a carboxylic acid into the correspondingacid chloride is effected by treatment of the carboxylic acid with areagent such as, for example, thionyl chloride or oxalyl chloride in aninert organic solvent such as dichloromethane, optionally in thepresence of a catalytic amount of dimethylformamide. The amide product123.23 is then converted into the triol 123.24. Using the aboveprocedures, but employing, in place of the hydroxylamine 123.20,different amino-substituted hydroxylamines, and/or differentcarboxy-substituted phosphonates, the products analogous to 123.24 areobtained.

EXAMPLE 124 Preparation of Representative Hydrocortisone Derivatives

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate group is attached to the 1′ or 2′ position of the pyrazolering, by means of a variable carbon chain is illustrated above. In thisprocedure, the BMD-protected enone 124.1 is reacted with ethyl formateand a base such as sodium hydride, in an inert solvent such as tolueneor dimethylformamide, as described in J. Am. Chem. Soc., 1964, 86, 1520,to afford the 2-formyl product 124.2. This compound is then reacted withan alkyl, aralkyl, aryl or heteroaryl hydrazine 124.3, in which thesubstituent X is either a phosphonate group or a group which issubsequently transformed into a phosphonate-containing substituent. Forexample, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and thelike. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles 124.4and 124.5. The pyrazole-forming reaction is performed between equimolaramounts of the reactants in an acidic solvent such as acetic acid, asdescribed in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles 124.4 and124.5 are then transformed via the BMD-protected intermediates 124.6 and124.7, into the phosphonates 124.8 and 124.9.

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate moiety is attached by means of a phenyl ring and an amidelinkage is illustrated above. In this procedure, the ketoaldehyde 124.2is reacted, as described above, with 3-carbomethoxyphenylhydrazine124.10 (Apin) to give the pyrazoles 124.11 and 124.12. The2′-substituted isomer 124.11 is then reacted with one molar equivalentof lithium hydroxide in aqueous dimethoxyethane, to produce thecarboxylic acid 124.13. The acid is then coupled, as described above,with a dialkyl aminomethyl phosphonate 124.14 (Interchim) to give theamide 124.15; deprotection then affords the triol 124.16.

Alternatively, the 1-substituted pyrazole 124.12 is hydrolyzed, asdescribed above, to the carboxylic acid 124.17. The product is thencoupled with a dialkyl 3-aminophenyl phosphonate 124.18 (J. Med. Chem.,1984, 27, 654) to yield after deprotection the triol amide 124.19. Usingthe above procedures, but employing, in place of the carbomethoxyphenylhydrazine 124.20, different carbomethoxy-substituted aralkyl, aryl orheteroaryl alkoxy hydrazines, and/or different dialkyl amino-substitutedphosphonates, the products analogous to the compounds 124.16 and 124.19are obtained.

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate group is attached by means of a phenyl group or a phenylgroup and a saturated or unsaturated carbon chain is illustrated above.In this procedure, the ketoaldehyde 124.2 is reacted, as describedabove, with 4-bromophenyl hydrazine 124.20 (J. Organomet. Chem., 1999,62, 581) to produce the pyrazoles 124.21 and 124.22. The 1′-substitutedisomer 124.21 is coupled, as described above, in the presence of apalladium catalyst, with a dialkyl butenyl phosphonate 124.23 (Org.Lett., 2001, 3, 217) to give the phosphonate 124.24. The product is thendeprotected to afford the triol 124.25. Optionally, the styrenoid doublebond present in the product 124.25 is reduced, as described above, toproduce the saturated analog 124.26.

Alternatively, the 2′-substituted pyrazole 124.22 is coupled, in thepresence of a palladium catalyst, with a dialkyl phosphite to preparethe phosphonate 124.27 which is deprotected to give the triol 124.28.The preparation of arylphosphonates by means of a coupling reactionbetween aryl bromides and dialkyl phosphites is described in J. Med.Chem., 35, 1371, 1992. This reaction is performed in an inert solventsuch as toluene, in the presence of a base such as triethylamine andtetrakis(triphenylphosphine)-palladium(0). Using the above procedures,but employing, in place of the bromophenyl hydrazine 124.20, differentbromo-substituted aralkyl, aryl or heteroaryl alkoxy hydrazines, and/ordifferent dialkyl alkenyl phosphonates, the products analogous to thecompounds 124.25, 124.26 and 124.28 are obtained.

EXAMPLE 125 Preparation of Representative Hydrocortisone Derivatives

The preparation of hydrocortisone phosphonate derivatives in which thephosphonate group is attached by means of a variable carbon linkage isillustrated above. In this procedure, the ketoaldehyde 124.2 is reactedwith hydrazine, to afford the pyrazole derivative 125.1. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 1964, 86, 1520. The reaction is performed in ethanol at refluxtemperature. The pyrazole product is then reacted with a bromomethylcompound 125.2, in which R² and X are as defined above, to yield thealkylation products 125.3 and 125.4. The alkylation of substitutedpyrazoles is described, for example, in Heterocyclic Chemistry, by T. L.Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 125.3 and 125.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 125.5 and 125.6, usingthe procedures described herein, and deprotection then affords thetriols 125.7 and 125.8.

Representative hydrocortisone derivatives can be prepared as illusratedabove. The pyrazole 125.1 is reacted, as described above, with one molarequivalent of a dialkyl 4-(bromomethyl)phenyl phosphonate 125.9 (WO2003042150) to give the alkylated pyrazoles 125.10 and 125.11.Deprotection then yields the triols 125.12 and 125.13.

Representative hydrocortisone derivatives can be prepared as illusratedabove. The pyrazole 125.1 is reacted, as described above, with2,5-bis(bromomethyl)thiophene 125.14 (Tet. 1999, 55, 4709) to give thepyrazoles 125.15 and 125.16. The products are subjected to an Arbuzovreaction, in which the bromomethyl substituent is converted into thedialkyl phosphonomethyl substituent, by reaction with a trialkylphosphite at 120°, to prepare, after deprotection of the side chain, thephosphonates 125.17 and 125.18. The Arbuzov reaction is described inHandb. Organophosphorus Chem., 1992, 115-72. In the procedure, thesubstrate is heated at from 60° to about 160° with a five to fifty-foldmolar excess of the trialkyl phosphite.

Using the above procedures, but employing, in place of the dibromide125.14, different dibromides, the products analogous to 125.17 and125.18 are obtained.

EXAMPLES 126-129 Dexamethasone Derivatives (124-126)

The structures of dexamethasone and representative phosphonate esters ofthe invention are shown below, in which the substituent R¹ is H, alkyl,alkenyl, aryl or aralkyl. These compounds incorporate a phosphonatemoiety (R¹O)₂P(O) connected to the nucleus by means of a variablelinking group, designated as “link” in the attached structures.

The synthesis of representative phosphonate derivatives ofhydrocortisone is outlined in Examples 126-129. In these Examples, itmay be necessary to protect certain reactive substituents from unwantedreactions by protection before the sequence described, and to deprotectthe substituents afterwards, according to the knowledge of one skilledin the art. Protection and deprotection of functional groups aredescribed, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990. The protectionand deprotection of steroidal ketones and alcohols is described inOrganic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J. A.Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactive substituentswhich may be protected are shown in the accompanying schemes as, forexample, [OH], [O], etc.

EXAMPLE 126 Preparation of Representative Dexamethasone Derivatives

The steroid side-chain is protected as a bis-methylenedioxy (BMD)moiety. In this sequence, Dexamethasone 126.1 is reacted withparaformaldehyde and an acid catalyst such as hydrochloric acid, asdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to yield the BMDderivative 126.2. The phosphonate moiety is then introduced, using theprocedures described below, to produce the phosphonate ester 126.3. TheBMD moiety is then hydrolyzed, for example by treatment with 50% aqueousacetic acid, as described in Protective Groups in Organic Synthesis, byT. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, toafford the triol 126.4

EXAMPLE 127 Preparation of Representative Dexamethasone Derivatives

The preparation of dexamethasone phosphonates in which the phosphonateis attached by means of an imino or iminoxy group and a variable carbonchain is illustrated above. In this procedure, the BMD-protectedderivative 126.2 is reacted with an amine or hydroxylamine 127.1, inwhich R² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group,optionally incorporating a heteroatom O, S or N, or a functional groupsuch as an amide, ester, oxime, sulfoxide or sulfone etc, or anoptionally substituted aryl, heteroaryl or aralkyl group, optionallyincorporating a heteroatom O, S or N, and X is either a phosphonategroup or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime. The preparation of oximes of steroidal 3-ketones is described inAnal. Bioch., 1978, 86, 133. and in J. Mass. Spectrom., 1995, 30, 497.The BMD-protected side-chain compound 127.2 is then converted into thetriol 127.3.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 127.4,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 127.5(Aldrich) to produce the ether 127.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 127.7.

The preparation of dexamethasone phosphonates in which the phosphonateis attached by means of an iminoxy group is illustrated above. In thisprocedure, the substrate 126.2 is reacted with a dialkyl phosphonomethylhydroxylamine 127.8, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime 127.9 which isdeprotected to afford the triol 127.10. The oxime forming reaction isperformed at ambient temperature in ethanol-acetic acid solution betweenequimolar amounts of the reactants. Using the above procedures, butemploying, in place of the hydroxylamine ether 127.8, different oximeethers 127.1, the corresponding products 127.3 are obtained.

The preparation of dexamethasone compounds in which the phosphonategroup is attached by means of a pyridyl methoxy group is illustratedabove. In this procedure, the dienone 126.2 is reacted, as describedabove, with O-(3-bromo-5-pyridylmethyl)hydroxylamine 127.11, prepared asdescribed above from 3-bromo-5-bromomethylpyridine (WO 9528400), togive, after deprotection of the side-chain, the oxime 127.12. Theproduct is then reacted, in the presence of a palladium catalyst, with adialkyl phosphite 127.13 to afford the phosphonate 127.14. Thepreparation of arylphosphonates by means of a coupling reaction betweenaryl bromides and dialkyl phosphites is described in J. Med. Chem., 35,1371, 1992. The reaction is performed in an inert solvent such astoluene, in the presence of a base such as triethylamine and a catalyticamount of tetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 127.12 is coupled with a dialkylvinylphosphonate 127.15 (Aldrich) to afford the phosphonate 127.16. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12,146, 1979. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 127.16 isreduced, for example by reaction with diimide, to produce the saturatedanalog 127.17. The reduction of olefinic bonds is described inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromopyridyloxy reagent 127.11, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 127.14, 127.16 and127.17 are obtained.

The preparation of dexamethasone phosphonates in which the phosphonateis attached by means of an imino group is illustrated above. In thisprocedure, the substrate 126.2 is reacted with a dialkyl 2-aminophenylphosphonate 127.18, (Syn., 1999, 1368) to give, after deprotection, theimine product 127.19. The reaction is conducted in a hydrocarbon solventsuch as toluene or xylene, at reflux temperature, in the presence of abasic catalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions. Using the aboveprocedures, but employing, in place of the 2-aminophenyl phosphonate127.18 different amino-substituted aryl or heteroaryl phosphonates,products analogous to 127.19 are obtained.

The preparation of dexamethasone phosphonates in which the phosphonateis attached by means of an oximino group and an amide linkage isillustrated above. In this procedure, the dienone 126.2 is reacted withO-(2-carboxyethyl)hydroxylamine 127.20 (J. Med. Chem., 1990, 33, 1423)to yield the oxime 127.21. The reaction of steroidal 1,4-dien-3-oneswith substituted hydroxylamines is described in J. Steroid Bioch., 1976,7, 795; the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The oximeis then reacted with a dialkyl aminomethyl phosphonate 127.22 (AsInEx),to yield the amide oxime 127.23. The preparation of amides fromcarboxylic acids and derivatives is described, for example, in OrganicFunctional Group Preparations, by S. R. Sandler and W. Karo, AcademicPress, 1968, p. 274, and Comprehensive Organic Transformations, by R. C.Larock, VCH, 1989, p. 972ff. The carboxylic acid is reacted with theamine in the presence of an activating agent, such as, for example,dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, N-hydroxysuccinimide orN-hydroxypyridone, in a non-protic solvent such as, for example,pyridine, DMF or dichloromethane, to afford the amide.

Alternatively, the carboxylic acid is first converted into an activatedderivative such as the acid chloride, anhydride, mixed anhydride,imidazolide and the like, and then reacted with the amine, in thepresence of an organic base such as, for example, pyridine, to affordthe amide. The conversion of a carboxylic acid into the correspondingacid chloride is effected by treatment of the carboxylic acid with areagent such as, for example, thionyl chloride or oxalyl chloride in aninert organic solvent such as dichloromethane, optionally in thepresence of a catalytic amount of dimethylformamide. The amide product127.23 is then converted into the triol 127.24.

Using the above procedures, but employing, in place of the hydroxylamine127.22, different carboxy-substituted hydroxylamines, and/or differentamino-substituted phosphonates, the products analogous to 127.24 areobtained.

EXAMPLE 128 Preparation of Representative Dexamethasone Derivatives

The preparation of the dexamethasone phosphonate esters in which thephosphonate group is attached to the 1′ or 2′ position of the pyrazolering, by means of an aromatic or heteroaromatic group, a heteroatom anda variable carbon chain is illustrated above. In this procedure, theBMD-protected dienone 126.2 is reduced to afford the 1,2-dihydro product128.1. The catalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product 128.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 128.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1-aryl pyrazoles128.4 and 128.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles128.4 and 128.5 are then transformed via the BMD-protected intermediates128.6 and 128.7, into the phosphonates 128.8 and 128.9.

The preparation of dexamethasone phosphonates in which the phosphonateis attached by means of a phenyl ring and an alkoxy or an acetyleniclinkage is illustrated above. In this procedure, the ketoaldehyde 128.2is reacted with 3-hydroxyphenyl-hydrazine 128.10 (Japanese patent JP03011081) to give the pyrazoles 128.11 and 128.12. The 2′-substitutedisomer 128.11 is then reacted in dichloromethane solution at ambienttemperature with one molar equivalent of trifluoromethylsulfonylchloride and dimethylaminopyridine, to yield the triflate 128.13. Theproduct is then reacted in toluene solution with a dialkyl propynylphosphonate 128.14 (Syn 1999, 2027), triethylamine and a catalyticamount of tetrakis(triphenylphosphine)palladium (0), to give theacetylenic product 128.15. The palladium-catalyzed coupling reaction ofaryl triflates with terminal acetylenes is described in WO 0230930. TheBMD protecting group is then removed to yield the triol 128.16.

Alternatively, the 1′-substituted pyrazole 128.12 is reacted, in aMitsonobu reaction, with a dialkyl 2-hydroxyethyl phosphonate 128.17(Epsilon) to afford the ether 128.18. The preparation of aromatic ethersby means of the Mitsonobu reaction is described, for example, inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.448, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335. Thephenol and the alcohol component are reacted together in an aproticsolvent such as, for example, tetrahydrofuran, in the presence of adialkyl azodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656. The product 128.18 is then deprotected to give thetriol 128.19. Using the above procedures, but employing differentacetylenic or hydroxyl-substituted phosphonates, the products analogousto 128.16 and 128.19 are obtained. The functionalization procedures areinterchangeable between the pyrazole substrates 128.11 and 128.12.

The preparation of dexamethasone phosphonates in which the phosphonategroup is attached by means of a benzyl group or a benzyl group and asaturated or unsaturated carbon chain is illustrated above. In thisprocedure, the ketoaldehyde 128.2 is reacted, as described above, with3-bromobenzyl hydrazine 128.20 (U.S. Pat. No. 4,370,339) to produce thepyrazoles 128.21 and 128.22. The 1′-substituted isomer 128.21 iscoupled, in the presence of a palladium catalyst, with a dialkylvinylphosphonate 128.23 (Aldrich) to give the phosphonate 128.24. Theproduct is then deprotected to afford the triol 128.25. Optionally, thestyrenoid double bond present in the product 128.25 is reduced, asdescribed above, to produce the saturated analog 128.26.

Alternatively, the 2′-substituted pyrazole 128.22 is coupled, in thepresence of a palladium catalyst, with a dialkyl phosphite to preparethe phosphonate 128.27 which is deprotected to give the triol 128.28.The preparation of arylphosphonates by means of a coupling reactionbetween aryl bromides and dialkyl phosphites is described in J. Med.Chem., 35, 1371, 1992. This reaction is performed in an inert solventsuch as toluene, in the presence of a base such as triethylamine andtetrakis(triphenylphosphine)-palladium(0).

Using the above procedures, but employing, in place of the bromobenzylreagent 128.20, different bromo-substituted aralkyl, aryl or heteroarylalkoxy hydrazines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 128.25, 128.26 and 128.28 areobtained.

EXAMPLE 129 Preparation of Representative Dexamethasone Derivatives

The preparation of dexamethasone phosphonate esters in which thephosphonate group is attached by means of a variable carbon linkage isillustrated above. In this procedure, the ketoaldehyde 128.2 is reactedwith hydrazine, to afford the pyrazole derivative 129.1. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 129.2, in which R² and X are as defined above, to yield thealkylation products 129.3 and 129.4. The alkylation of substitutedpyrazoles is described, for example, in Heterocyclic Chemistry, by T. L.Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 129.3 and 129.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 129.5 and 129.6, usingthe procedures described herein, and deprotection then affords thetriols 129.7 and 129.8.

The preparation of representative compounds of the invention isillustrated above. The pyrazole 129.1 is reacted, as described above,with one molar equivalent of a dialkyl bromoacetonyl phosphonate 129.9(Tet., 1978, 34, 649) to give the alkylated pyrazoles 129.10 and 129.11.Deprotection then yields the triols 129.12 and 129.13.

The preparation of representative compounds of the invention isillustrated above. The pyrazole 129.1 is reacted, as described above,with 1,4-bis(bromomethyl)benzene 129.14 to give the pyrazoles 129.15 and129.16. The products are subjected to an Arbuzov reaction, in which thebromomethyl substituent is converted into the dialkyl phosphonomethylsubstituent, by reaction with a trialkyl phosphite at 120°, to prepare,after deprotection of the side chain, the phosphonates 129.17 and129.18. The Arbuzov reaction is described in Handb. OrganophosphorusChem., 1992, 115-72. In the procedure, the substrate is heated at from60° to about 160° with a five to fifty-fold molar excess of the trialkylphosphite. Using the above procedures, but employing, in place of thedibromide 129.14, different dibromides, the products analogous to 129.17and 129.18 are obtained.

EXAMPLES 130-133 Beclomethasone Derivatives

The structures of Beclomethasone (British Patent GB 912378) and Vanceril(U.S. Pat. No. 4,024,131) and representative phosphonate esters of theinvention are shown below, in which the substituent R¹ is H, alkyl,alkenyl, aryl or aralkyl. These compounds incorporate a phosphonatemoiety (R¹O)₂P(O) connected to the nucleus by means of a variablelinking group, designated as “link” in the attached structures.

The synthesis of representative phosphonate derivatives ofbeclomethasone is outlined in Examples 130-133. In these Examples, itmay be necessary to protect certain reactive substituents from unwantedreactions by protection before the sequence described, and to deprotectthe substituents afterwards, according to the knowledge of one skilledin the art. Protection and deprotection of functional groups aredescribed, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990. The protectionand deprotection of steroidal ketones and alcohols is described inOrganic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J. A.Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactive substituentswhich may be protected are shown in the accompanying schemes as, forexample, [OH], [O], etc.

EXAMPLE 130 Preparation of Representative Beclomethasone Derivatives

Ther preparation of representative beclomethasone derivatives of theinvention is illustrated above. The propionate esters are hydrolyzed,for example by reaction with two molar equivalents of lithium hydroxidein aqueous dimethoxyethane solution at ambient temperature, to give thetriol 130.2. The product is then reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in ProtectiveGroups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative 130.3. Thephosphonate moiety is then introduced, using the procedures describedbelow, to produce the phosphonate ester 130.4. Prior to hydrolysis ofthe BMD protecting group, the 11-hydroxyl group is protected. Theprotecting group is selected so that it is stable to the conditionsrequired for removal of the BMD group, and so that it is removablewithout affecting the subsequently introduced 17, 21-diester moiety. Forexample, the 11-hydroxyl group is protected by conversion to the4-azidobutyrate ester, by reaction with 4-azidobutyryl chloride inpyridine. The 11-azidobutyrate group is then removed from the diester130.7 by reaction with triphenylphosphine, as described in Bull. Soc.Chem. Jpn., 59, 1296, 1986. Alternatively, the 11-hydroxyl group isprotected by conversion to the 2-(trimethylsilyl)ethyl carbonate, byreaction with 2-(trimethylsilyl)ethyl carbonyl chloride and pyridine.The 2-(trimethylsilyl) carbonate is removed from the diester 130.7 byreaction with tetrabutylammonium fluoride in tetrahydrofuran at ambienttemperature, as described in Tet. Lett., 22, 969, 1981.

Alternatively, the 11-hydroxyl group is protected by conversion to thetrichloroacetyl ester, by reaction with trichloroacetyl chloride indimethylformamide-pyridine. The trichloroacetyl ester is removed byreaction with ethanolic ammonia at ambient temperature, as described inColl. Czech. Chem. Commun., 27, 2567, 1962.

The BMD moiety in the protected product 130.5 is then hydrolyzed, forexample by treatment with 50% aqueous acetic acid, as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the triol 130.6. Thelatter compound is then acylated, for example by reaction with propionicacid and dicyclohexyl carbodiimide in dimethylformamide at ambienttemperature, or by reaction with propionyl chloride and triethylamine indichloromethane, to produce the dipropionate 130.7. Deprotection of the11-hydroxyl group, as described above, then affords the diester 130.8.The protected 17,21-diol 130.8 is deprotected, as described above, toafford the 11,17,21 trihydroxy compound 130.9.

Alternatively, the 20-ketone group is protected as the diethylamineadduct by reaction with titanium tetrakis(diethylamide), as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. MWuts, Wiley, Second Edition 1990, p. 219.

EXAMPLE 131 Preparation of Representative Beclomethasone Derivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the BMD-protected derivative 130.3is reacted with an amine or hydroxylamine 131.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, to afford the imine or iminoxy product 131.2.The reaction is conducted between equimolar amounts of the reactants inan aprotic solvent such as pyridine or xylene, or in an alcoholicsolvent such as ethanol, optionally in the presence of an acid catalyst,to give the imine or oxime. The preparation of oximes of steroidal3-ketones is described in Anal. Bioch., 1978, 86, 133. and in J. Mass.Spectrom., 1995, 30, 497. The BMD-protected side-chain compound 131.2 isthen converted into the diester 131.4 and the triol 131.3.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated above. In this procedure, a phosphonate 131.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine 131.6 (Aldrich) to produce the ether131.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine, to give the product 131.7. Deprotection, forexample by treatment with trifluoroacetic acid, then gives thehydroxylamine ether 131.8.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 130.3 is reacted with a dialkyl phosphonomethyl hydroxylamine131.9, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford, after protection-deprotectionand side chain acylation, the oxime ethers 131.10 and 131.11. The oximeforming reaction is performed at ambient temperature in pyridinesolution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of the oxime ether131.9, different oxime ethers 131.8, the corresponding products 131.3and 131.4 are obtained.

The preparation of phosphonates incorporating an iminoxy group, by meansof the reaction between the substrate 130.3 andO-2-(3-bromophenoxy)ethoxyhydroxylamine 131.12, prepared as describedabove from 2-(3-bromophenoxy)ethyl bromide (French patent FR 1481052).The resultant oxime ether 131.13 is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite 131.14 to afford thephosphonate 131.15. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 35, 1371, 1992. The reaction is performed inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)-palladium(0). The BMD-protected product131.15 is then converted into the triol 131.16 and the dipropionate131.17.

Alternatively, the bromo-substituted product 131.13 is coupled, in apalladium-catalyzed Heck reaction, with a dialkyl vinyl phosphonate131.18 (Aldrich) to give the unsaturated phosphonate 131.19. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12,146, 1979. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)-palladium(0)or a palladium(II) catalyst such as palladium(II) acetate, andoptionally in the presence of a base such as triethylamine or potassiumcarbonate. The product 131.19 is then converted into the triol 131.20and the dipropionate 131.21.

Optionally, the styrenoid double bond present in the products 131.20 and131.21 is reduced, for example by reaction with diimide, to produce thesaturated analogs 131.22 and 131.23. The reduction of olefinic bonds isdescribed in Comprehensive Organic Transformations, by R. C. Larock,VCH, 1989, p. 6ff. The transformation is effected by means of catalytichydrogenation, for example using a palladium on carbon catalyst andhydrogen or a hydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromophenoxyreagent 131.12, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 131.16, 131.17, 131.20, 131.21,131.22 and 131.23 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate 130.3 is reacted with a dialkyl 4-amino-2-thienyl phosphonate131.14, prepared by the palladium-catalyzed coupling reaction between adialkyl phosphite and 2-bromo-4-aminothiophene (Tet., 1987, 43, 3295) togive, after deprotection and side chain acylation, the imine products131.25 and 131.26. The reaction is conducted in a hydrocarbon solventsuch as toluene or xylene, at reflux temperature, in the presence of abasic catalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions, to give theproducts 131.25 and 131.26.

Using the above procedures, but employing, in place of the3-aminothienyl phosphonate 131.24 different amino-substituted aryl orheteroaryl phosphonates, products analogous to 131.25 and 131.26 areobtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an amide linkage is illustrated above. Inthis procedure, the dienone 130.3 is reacted withO-(2-aminoethyl)hydroxylamine 131.27 (Bioorganicheskaya Khim., 1986, 12,1662) to yield the oxime 131.28. The reaction of steroidal1,4-dien-3-ones with hydroxylamines is described in J. Steroid Bioch.,1976, 7, 795; the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The oximeis then reacted with a dialkyl phosphonoacetic acid 131.29 (Aldrich), toyield the amide oxime 131.30. The preparation of amides from carboxylicacids and derivatives is described, for example, in Organic FunctionalGroup Preparations, by S. R. Sandler and W. Karo, Academic Press, 1968,p. 274, and Comprehensive Organic Transformations, by R. C. Larock, VCH,1989, p. 972ff. The carboxylic acid is reacted with the amine in thepresence of an activating agent, such as, for example,dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, N-hydroxysuccinimide orN-hydroxypyridone, in a non-protic solvent such as, for example,pyridine, DMF or dichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The amide product 131.30 is then converted into the triol 131.31 and thedipropionate 131.32. Using the above procedures, but employing, in placeof the hydroxylamine 131.27, different amino-substituted hydroxylamines,and/or different carboxy-substituted phosphonates, the productsanalogous to 131.31 and 131.32 are obtained.

EXAMPLE 132 Preparation of Representative Beclomethasone Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illustrated above. In this procedure, Vanceril 132.1 is reducedto afford the 1,2-dihydro product, 132.2. The catalytic hydrogenationreaction is effected by the use of tris(triphenylphosphine)rhodium (I)chloride, for example as described in J. Med. Chem., 2001, 44, 602. Theproduct is then reacted with ethyl formate and a base such as sodiumhydride, in an inert solvent such as toluene or dimethylformamide, asdescribed in Australian Patent Application 275950409, to afford the2-formyl product 132.3. Optionally, the substrate 132.1 is protected,for example as described above, prior to the reduction and formylationreactions, as described in J. Am. Chem. Soc., 1964, 86, 1520. The2-formyl product is then reacted with an aryl or heteroaryl hydrazine132.4, in which the substituent X is either a phosphonate group or agroup which is subsequently transformed into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxyl and the like. The reaction yields the isomeric 2′- and 1-arylpyrazoles 132.5 and 132.6. The pyrazole-forming reaction is performedbetween equimolar amounts of the reactants in an acidic solvent such asacetic acid, as described in J. Am. Chem. Soc., 1964, 86, 1520. Thepyrazoles 132.5 and 132.6 are then transformed, respectively, into thephosphonates 132.7, 132.8, 132.9 and 132.10.

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl group is illustrated above. In this sequence, theketoaldehyde 132.3 is reacted, as described above, with3-bromophenylhydrazine 132.11 (Fluka), to give the isomeric pyrazoleproducts 132.12 and 132.13. The products are then reacted, as describedabove, with a dialkyl phosphite HP(O)(^(OR) ¹)₂ and a palladiumcatalyst, to afford respectively the phosphonates 132.15 and 132.17.Basic hydrolysis, as described above, then yields the triols 132.14 and132.16.

Using the above procedures, but employing, in place of 3-bromophenylhydrazine, different bromoaryl or bromoheteroaryl hydrazines 132.4, theproducts analogous to 132.7, 132.8, 132.9 and 132.10 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an aromatic or heteroaromatic group and a saturated orunsaturated alkyl chain is illustrated above. In this procedure, thebromophenyl-substituted pyrazole 132.12 is coupled in a Heck reaction,as described above, with a dialkyl 4-vinylphenyl phosphonate 132.18(Macromolecules, 1998, 31, 2918) to give the unsaturated phosphonateproduct 132.20. Basic hydrolysis then gives the triol 132.19.Optionally, the products are reduced, as described above, to give thesaturated analogs 132.21 and 132.22. Application of the above proceduresto the isomeric bromophenyl pyrazole 132.13 affords the productsisomeric with 132.19, 132.20, 132.21 and 132.22. Using the aboveprocedures, but employing, in place of the phosphonate 132.18, differentdialkyl alkenyl phosphonates, and/or different bromoaryl or heteroarylpyrazoles 132.5 or 132.6 (X=Br) the products analogous to 132.19,132.20, 132.21 and 132.22 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an aryl or heteroaryl group and an amide linkage. In thisprocedure, 3-carboxyphenylhydrazine 132.23 (Apin) is reacted indimethylformamide solution at ambient temperature with the ketoaldehyde132.3, to form the isomeric pyrazoles 132.24 and 132.25. The product132.24 is then coupled, as described above, with a dialkyl 3-aminopropylphosphonate 132.26 (Synthelec) to give the amide 132.27. Basichydrolysis then produces the triol 132.27. Alternatively, the carboxylicacid 132.25 is reacted with a dialkyl 4-aminophenyl phosphonate 132.29(Epsilon) to prepare the triol 132.30 and the diester 132.31. Using theabove procedures, but employing, in place of the carboxy-substitutedhydrazine 132.23, different carboxy-substituted aryl or heteroarylhydrazines, the products analogous to 132.27, 132.28, 132.30 and 132.31are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of a pyrimidinyl group, either directly or with a saturated orunsaturated carbon chain is illustrated above. In this procedure,2,5-dibromopyrimidine 132.32 (Chem. Lett., 1992, 583) is reacted withhydrazine to afford 5-bromo-2-pyrimidinyl hydrazine 132.33. Thepreparation of pyrimidinyl hydrazines by the reaction of2-halopyrimidines with hydrazine is described in J. Med. Chem., 2002,45, 5397. The product is then reacted with the ketoaldehyde 132.3 toyield the isomeric pyrazoles 132.34 and 132.35. The compound 132.34 iscoupled, as described above, with a dialkyl phosphite to afford thephosphonate 132.37; basic hydrolysis then gives the triol 132.36.

Alternatively, the isomeric pyrazole 132.35 is coupled, as describedabove, with a dialkyl vinyl phosphonate 132.38 to prepare thephosphonate 132.39. Basic hydrolysis then produces the triol 132.40, andreduction of the double bond, as described above, yields the diester132.41 and the triol 132.42.

Using the above procedures, but employing, in place of the pyrimidinylhydrazine 132.33, different bromo-substituted aryl or heteroarylhydrazines, and/or different alkenyl phosphonates, the productsanalogous to 132.36, 132.37, 132.39, 132.40, 132.41 and 132.42 areobtained.

EXAMPLE 133 Preparation of Representative Beclomethasone Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde 132.3 is reacted with hydrazine, toafford the pyrazole derivative 133.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The resulting pyrazole is then reacted with abis(bromomethyl) reagent 133.2, in which R² is as defined above, toproduce the isomeric 2′ and 1′ alkylation products 133.3 and 133.4respectively. The alkylation of substituted pyrazoles is described, forexample, in Heterocyclic Chemistry, by T. L. Gilchrist, Longman, 1992,p. 309. The reaction is performed between equimolar amounts of thesubstrates in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theisomer 133.3 is reacted, in an Arbuzov reaction, with a trialkylphosphite to yield the phosphonate 133.5: basic hydrolysis then givesthe triol 133.6. The preparation of phosphonates by means of thereaction between an alkyl halide and a trialkyl phosphite is describedin Handb. Organophosphorus Chem., 1992, 115-72. The substrate and anexcess of the phosphite are heated at ca. 120° to effect the conversion.Application of the above procedure to the isomeric 1′-substitutedpyrazole yields the corresponding isomeric products.

Alternatively, the bromomethyl-substituted pyrazole 133.4 is reactedwith a dialkyl hydroxy, mercapto or amino-substituted phosphonate 133.7to afford the ether, thioether or amine products 133.8 and 133.9. Thedisplacement reaction is performed in a polar solvent such asdimethylformamide or acetonitrile, at from ambient temperature to about70°, in the presence of an inorganic base such as potassium carbonate,or an organic base such as dimethylaminopyridine. Application of theabove procedure to the isomeric 2′-substituted pyrazole yields thecorresponding isomeric products.

Representative compounds of the invention can be prepared is illustratedabove. The pyrazole 133.1 is reacted, in dimethylformamide solution atca. 90°, with a dialkyl 1,3-bis(bromomethyl)Cyclopentane 133.10 (Bull.Soc. Chim. FR., 1975, 1295) and dimethylaminopyridine, to yield theisomeric alkylation products 133.11 and 133.12. The 2′-substitutedcompound 133.11 is then reacted with ten molar equivalents of a trialkylphosphite at 100°, to yield the phosphonate 133.14. Basic hydrolysisproduces the triol 133.13.

Alternatively, the 1-substituted isomer 133.12 is reacted at 70° indimethylformamide solution with one molar equivalent of a dialkylaminomethyl phosphonate 133.15 (Interchim) and potassium carbonate, toprepare the amine phosphonate 133.17; basic hydrolysis affords the triol133.16. Application of the procedures to the isomeric bromomethylcompound 133.11 affords the corresponding isomeric products.

Representative compounds of the invention can be prepared is illustratedabove. The pyrazole 133.1 is reacted, as described above, with2,5-bis(bromomethyl)furan 133.18 (Tet., 1999, 55, 4709) to give thesubstituted pyrazoles 133.19 and 133.20. The 2′-substituted compound133.19 is then reacted, as described above, with a trialkyl phosphite toproduce the diester phosphonate 133.21 and the triol 133.22.

Alternatively, the 1′ isomer 133.20 is reacted, as described above, witha dialkyl 3-mercaptopropyl phosphonate 133.23 (WO 2000077101) to givethe diester 133.24 and the triol 133.25.

Using the above procedure, but employing, in place of the mercaptoethylphosphonate 133.23, different hydroxy, mercapto or amino-substitutedphosphonates, the corresponding ether, thioether or amino products areobtained.

EXAMPLE 134 Preparation of Representative Compounds of Formulae 133-138

Representative compounds of Formulae 133-138 can be prepared asillustrated above. Synthetic methodology towards compounds such as theseis described by Westwood et al, J. Med. Chem., 1996, 39, 4608-4621.

The preparation of an intermediate aniline useful in the above generalprocedures is illustrated below.

The preparation of an intermediate alkyne that can also be used in theabove general procedures is illustrated below.

EXAMPLES 135-138 Methylprednisolone Suleptanate Derivatives

The structures of Methylprednisolone suleptanate (WO 8900558) andrepresentative phosphonate esters of the invention are shown below, inwhich the substituent R¹ is H, alkyl, alkenyl, aryl or aralkyl. Thesecompounds incorporate a phosphonate moiety (R¹O)₂P(O) connected to thenucleus by means of a variable linking group, designated as “link” inthe attached structures.

The synthesis of representative phosphonate derivatives ofmethylprednisolone suleptanate is outlined in Examples 135-138. In theseExamples, it may be necessary to protect certain reactive substituentsfrom unwanted reactions by protection before the sequence described, andto deprotect the substituents afterwards, according to the knowledge ofone skilled in the art. Protection and deprotection of functional groupsare described, for example, in Protective Groups in Organic Synthesis,by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990. Theprotection and deprotection of steroidal ketones and alcohols isdescribed in Organic Reactions in Steroid Chemistry, Vol. 1, J. Friedand J. A. Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactivesubstituents which may be protected are shown in the accompanyingschemes as, for example, [OH], [O], etc.

EXAMPLE 135 Preparation of Representative Methylprednisolone SuleptanateDerivatives

Representative compounds of the invention can be prepared as illusrratedabove. The steroid side-chain is protected as a bis-methylenedioxy (BMD)moiety. In this sequence, methylprednisolone 135.1 is reacted withparaformaldehyde and an acid catalyst such as hydrochloric acid, asdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to yield the BMDderivative 135.2. The phosphonate moiety is then introduced, using theprocedures described below, to produce the phosphonate ester 135.3. TheBMD moiety is then hydrolyzed, for example by treatment with 50% aqueousacetic acid, as described in Protective Groups in Organic Synthesis, byT. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, toafford the triol 135.4. The triol is then converted into the21-suleptanate ester as described in WO 8900558. In this procedure, amixed anhydride prepared by reacting suleptanic acid with pivaloylchloride, in the presence of a base such as triethylamine, is reactedwith the 21-hydroxy steroid 135.4 to prepare the 21-suleptanate ester135.5.

EXAMPLE 136 Preparation of Representative Methylprednisolone SuleptanateDerivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillusrrated above. In this procedure, the BMD-protected derivative 135.2is reacted with an amine or hydroxylamine 136.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 1978, 86, 133. and in J. Mass. Spectrom., 1995, 30, 497. TheBMD-protected side-chain compound 136.2 is then converted into the triol136.3a, and then to the suleptanate 136.3b.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 136.4,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 136.5(Aldrich) to produce the ether 136.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 136.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illusrrated above. In this procedure, thesubstrate 135.2 is reacted with a dialkyl phosphonomethyl hydroxylamine136.8, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime 136.9 which isdeprotected to afford the triol 136.10a from which the suleptanate ester136.10b is prepared. The oxime forming reaction is performed at ambienttemperature in ethanol-acetic acid solution between equimolar amounts ofthe reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 136.8, different oxime ethers 136.1, the corresponding products136.3b are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a phenoxyethoxy oxime group is illusrrated above. In thisprocedure, the dienone 135.2 is reacted, as described above, withO-(3-bromophenoxyethyl)hydroxylamine 136.11, prepared as described abovefrom 3-bromophenoxyethyl bromide (FR 1481052) and BOC-protectedhydroxylamine, to give, after deprotection of the side-chain, the oxime136.12. The product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphite 136.13 to afford the phosphonate136.14a. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem., 35, 1371, 1992. The reaction is performed in an inertsolvent such as toluene, in the presence of a base such as triethylamineand a catalytic amount of tetrakis(triphenylphosphine)palladium(0). The21-hydroxy group is then converted into the 21-suleptanate product136.14b.

Alternatively, the bromo compound 136.12 is coupled with a dialkylpropenylphosphonate 136.15 (Aldrich) to afford the phosphonate 136.16a.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12,146, 1979. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 136.16a isreduced, for example by reaction with diimide, to produce the saturatedanalog 136.17a. The reduction of olefinic bonds is described inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane. The products136.16a and 136.17a are then converted into the suleptanate esters136.16b and 136.17b.

Using the above procedures, but employing, in place of thebromophenoxyethoxy reagent 136.11, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 136.14b, 136.16band 136.17b are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate 135.2 is reacted with a dialkyl 4-aminophenyl phosphonate136.18, (Epsilon) to give, after deprotection, the imine product136.19a. The reaction is conducted in a hydrocarbon solvent such astoluene or xylene, at reflux temperature, in the presence of a basiccatalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions. The product is thenconverted into the suleptanate ester 136.19b.

Using the above procedures, but employing, in place of the 4-aminophenylphosphonate 136.18 different amino-substituted aryl or heteroarylphosphonates, products analogous to 136.19b are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an amide linkage is illusrrated above. Inthis procedure, the dienone 135.2 is reacted withO-(4-aminobutyl)hydroxylamine 136.20 (Pol. J. Chem., 1981, 55, 1163) toyield the oxime 136.21. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch., 1976, 7,795; the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The oximeis then coupled with a dialkyl phosphonoacetic acid 136.22 (Aldrich), toyield the amide oxime 136.23. The preparation of amides from carboxylicacids and derivatives is described, for example, in Organic FunctionalGroup Preparations, by S. R. Sandler and W. Karo, Academic Press, 1968,p. 274, and Comprehensive Organic Transformations, by R. C. Larock, VCH,1989, p. 972ff. The carboxylic acid is reacted with the amine in thepresence of an activating agent, such as, for example,dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, N-hydroxysuccinimide orN-hydroxypyridone, in a non-protic solvent such as, for example,pyridine, DMF or dichloromethane, to afford the amide.

Alternatively, the carboxylic acid is first converted into an activatedderivative such as the acid chloride, anhydride, mixed anhydride,imidazolide and the like, and then reacted with the amine, in thepresence of an organic base such as, for example, pyridine, to affordthe amide. The conversion of a carboxylic acid into the correspondingacid chloride is effected by treatment of the carboxylic acid with areagent such as, for example, thionyl chloride or oxalyl chloride in aninert organic solvent such as dichloromethane, optionally in thepresence of a catalytic amount of dimethylformamide. The amide product136.23 is then converted into the suleptanate 136.24b.

Using the above procedures, but employing, in place of the hydroxylamine136.22, different amino-substituted hydroxylamines, and/or differentcarboxy-substituted phosphonates, the products analogous to 136.24b areobtained.

EXAMPLE 137 Preparation of Representative Methylprednisolone SuleptanateDerivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illusrrated above. In this procedure, the BMD-protected dienone135.2 is reduced to afford the 1,2-dihydro product 137.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product 137.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 137.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles137.4 and 137.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles137.4 and 137.5 are then transformed via the BMD-protected intermediates137.6 and 137.7, into the phosphonate suleptanates 137.8b and 137.9b.

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl ring and an alkoxy or an alkenyl linkage isillusrrated above. In this procedure, the ketoaldehyde 137.2 is reacted,as described above, with 4-hydroxyphenylhydrazine 137.10 (Epsilon) togive the pyrazoles 137.11 and 137.12. The 2′-substituted isomer 137.11is then reacted in dimethylformamide solution at ambient temperaturewith one molar equivalent of 1,4-dibromobut-2-ene anddimethylaminopyridine, to yield the bromoether 137.13. The product isthen reacted at 120° in an Arbuzov reaction with a trialkyl phosphite137.14 to give the phosphonate product 137.15. The Arbuzov reaction, inwhich an alkyl bromide is transformed into the correspondingphosphonate, by heating at from 60° to about 150° with a trialkylphosphite, is described in Handb. Organophosphorus Chem., 1992, 115-72.The BMD protecting group is then removed and the product is acylated toyield the suleptanate ester triol 137.16b.

Alternatively, the 1′-substituted pyrazole 137.12 is reacted, in aMitsonobu reaction, with a dialkyl 2-hydroxymethyl phosphonate 137.17(Aldrich) to afford the ether 137.18. The preparation of aromatic ethersby means of the Mitsonobu reaction is described, for example, inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.448, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335. Thephenol and the alcohol or thiol component are reacted together in anaprotic solvent such as, for example, tetrahydrofuran, in the presenceof a dialkyl azodicarboxylate and a triarylphosphine, to afford theether or thioether products. The procedure is also described in Org.React., 1992, 42, 335-656. The product 137.18 is then deprotected togive the triol 137.19a, and the latter compound is acylated to affordthe suleptanate 137.19b.

Using the above procedures, but employing different dibromides orhydroxyl-substituted phosphonates, the products analogous to 137.16b and137.19b are obtained. The functionalization procedures areinterchangeable between the pyrazole substrates 137.11 and 137.12.

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl ring or a phenyl ring and a saturated orunsaturated carbon chain is illustrated above. In this procedure, theketoaldehyde 137.2 is reacted, as described above, with 4-bromophenylhydrazine 137.20 (J. Organomet. Chem., 1999, 62, 581) to produce thepyrazoles 137.21 and 137.22. The 1′-substituted isomer 137.21 iscoupled, in the presence of a palladium catalyst, with a dialkylvinylphosphonate 137.23 (Aldrich) to give the phosphonate 137.24. Theproduct is then deprotected to afford the triol 137.25a which isconverted into the suleptanate 137.25b. Optionally, the styrenoid doublebond present in the product 137.25b is reduced, as described above, toproduce the saturated analog 137.26b.

Alternatively, the 2′-substituted pyrazole 137.22 is coupled, in thepresence of a palladium catalyst, with a dialkyl phosphite to preparethe phosphonate 137.27 which is deprotected, and the product is acylatedto give the suleptanate ester 137.28b. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem., 35, 1371, 1992.This reaction is performed in an inert solvent such as toluene, in thepresence of a base such as triethylamine andtetrakis(triphenylphosphine)palladium(0).

Using the above procedures, but employing, in place of the bromophenylhydrazine 137.20, different bromo-substituted aralkyl, aryl orheteroaryl alkoxy hydrazines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 137.25b, 137.26band 137.28b are obtained.

EXAMPLE 138 Preparation of Representative Methylprednisolone SuleptanateDerivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde 137.2 is reacted with hydrazine, toafford the pyrazole derivative 138.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 138.2, in which R² and X are as defined above, to yield thealkylation products 138.3 and 138.4. The alkylation of substitutedpyrazoles is described, for example, in Heterocyclic Chemistry, by T. L.Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 138.3 and 138.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 138.5 and 138.6, usingthe procedures described herein, and deprotection/acylation then affordsthe suleptanate esters 138.7b and 138.8b.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 138.1 is reacted in tetrahydrofuran solution, asdescribed above, with one molar equivalent of a dialkyl bromobutylphosphonate 138.9 (Synthesis, 1994, 9, 909) and lithiumhexamethyldisilazide to give the alkylated pyrazoles 138.10 and 138.11.Deprotection/acylation then yields the suleptanates 138.12b and 138.13b.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 138.1 is reacted in tetrahydrofuran solution, asdescribed above, with 1,2-bis(bromomethyl)Cyclopropane 138.14 (Tet.,1997, 53, 10459) to give the pyrazoles 138.15 and 138.16. The productsare subjected to an Arbuzov reaction, in which the bromomethylsubstituent is converted into the dialkyl phosphonomethyl substituent,by reaction with a trialkyl phosphite at 120°, to prepare, afterdeprotection of the side chain and acylation, the suleptanatephosphonates 138.17b and 138.18b. The Arbuzov reaction is described inHandb. Organophosphorus Chem., 1992, 115-72. In the procedure, thesubstrate is heated at from 60° to about 160° with a five to fifty-foldmolar excess of the trialkyl phosphite.

Using the above procedures, but employing, in place of the dibromide138.14, different dibromides, the products analogous to 138.17b and138.18b are obtained.

EXAMPLES 139-142 Prednisone Derivatives

The structures of prednisone (U.S. Pat. No. 2,897,464) andrepresentative phosphonate esters of the invention are shown below, inwhich the substituent R¹ is H, alkyl, alkenyl, aryl or aralkyl. Thesecompounds incorporate a phosphonate moiety (R¹O)₂P(O) connected to thenucleus by means of a variable linking group, designated as “link” inthe attached structures.

The synthesis of representative phosphonate derivatives of prednisone isoutlined in Examples 139-142. In these Examples, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 139 Preparation of Representative Prednisone Derivatives

Representative compounds of the invention can be prepared as illustratedabove. The steroid side-chain is protected as a bis-methylenedioxy (BMD)moiety. In this sequence, prednisone is reacted with paraformaldehydeand an acid catalyst such as hydrochloric acid, as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to yield the BMD derivative139.2. The phosphonate moiety is then introduced, using the proceduresdescribed below, to produce the phosphonate ester 139.3. The BMD moietyis then hydrolyzed, for example by treatment with 50% aqueous aceticacid, as described in Protective Groups in Organic Synthesis, by T. W.Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to affordthe triol 139.4. Optionally, depending on the nature of the reactions tobe employed, the 11-ketone group in the BMD compound 139.2 is protectedbefore introduction of the phosphonate group. The ketone is protected,for example, as the cyclic ethylene ketal, by reaction in toluenesolution at reflux temperature with ethylene glycol and an acidcatalyst, as described in J. Am. Chem. Soc., 77, 1904, 1955.Deprotection is effected by reaction with pyridinium tosylate in aqueousacetone, as described in J. Chem. Soc., Chem. Comm., 1351, 1987.

Alternatively, the 11-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 139.2 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 50, 102, 1970. The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 101, 5841, 1979.

Alternatively, the 11-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 139.2 is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc., Chem. Comm., 406,1983, to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The 11-protected BMD compound 139.5 is then converted, using theprocedures described below, into the phosphonate 139.6. Deprotectionthen yields the 11-keto diol 139.4.

EXAMPLE 140 Preparation of Representative Prednisone Derivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the doubly-protected derivative139.5 is reacted with an amine or hydroxylamine 140.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 1978, 86, 133. and in J. Mass. Spectrom., 1995, 30, 497. Theprotecting groups are then removed to afford the ketodiol 140.3.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 140.4,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 140.5(Aldrich) to produce the ether 140.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 140.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 139.5, in which the 11-ketone is protected as the dimethylhydrazone, is reacted with a dialkyl phosphonomethyl hydroxylamine140.8, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime 140.9 which isdeprotected by reaction with 50% aqueous acetic acid, to afford the diol140.10. The oxime forming reaction is performed at ambient temperaturein ethanol-acetic acid solution between equimolar amounts of thereactants.

Using the above procedures, but employing, in place of the hydroxylamineether 140.8, different oxime ethers 140.1, the corresponding products140.3 are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a benzyloxime group is illustrated above. In this procedure,the dienone 139.5 is reacted, as described above, withO-(2-bromobenzyl)hydroxylamine 140.11, prepared as described above from2-bromobenzyl bromide, to give, after deprotection, the oxime 140.12.The product is then reacted, in the presence of a palladium catalyst,with a dialkyl phosphite 140.13 to afford the phosphonate 140.14. Thepreparation of arylphosphonates by means of a coupling reaction betweenaryl bromides and dialkyl phosphites is described in J. Med. Chem., 35,1371, 1992. The reaction is performed in an inert solvent such astoluene, in the presence of a base such as triethylamine and a catalyticamount of tetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 140.12 is coupled with a dialkylvinylphosphonate 140.15 (Aldrich) to afford the phosphonate 140.16. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12,146, 1979. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 140.16 isreduced, for example by reaction with diimide, to produce the saturatedanalog 140.17. The reduction of olefinic bonds is described inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the benzyloxyreagent 140.11, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 140.14, 140.16 and 140.17 areobtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate 139.5 is reacted with a dialkyl 4-aminophenyl phosphonate140.18, (Epsilon) to give, after deprotection, the imine product 140.19.The reaction is conducted in a hydrocarbon solvent such as toluene orxylene, at reflux temperature, in the presence of a basic catalyst suchas sodium methoxide, or an acid catalyst such as p-toluenesulfonic acid,under azeotropic conditions.

Using the above procedures, but employing, in place of the 4-aminophenylphosphonate 140.18 different amino-substituted aryl or heteroarylphosphonates, products analogous to 140.19 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an ether linkage is illustrated above. Inthis procedure, the dienone 139.5 is reacted withO-(2-hydroxyyethyl)hydroxylamine 140.20 (J. Chem. Soc., Chem. Comm.,1986, 903) to yield the oxime 140.21. The reaction of steroidal1,4-dien-3-ones with substituted hydroxylamines is described in JSteroid Bioch., 1976, 7, 795; the reaction is performed betweenequimolar amounts of the reactants in a polar organic solvent such aspyridine or methanol, optionally in the presence of acetic acid orsodium acetate. The oxime is then reacted in a Mitsonobu reaction with adialkyl 4-hydroxyphenyl phosphonate 140.22 (Epsilon), to yield the etheroxime 140.23. The preparation of aromatic ethers by means of theMitsonobu reaction is described, for example, in Comprehensive OrganicTransformations, by R. C. Larock, VCH, 1989, p. 448, and in AdvancedOrganic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum,2001, p. 153-4 and in Org. React., 1992, 42, 335. The phenol and thealcohol or thiol component are reacted together in an aprotic solventsuch as, for example, tetrahydrofuran, in the presence of a dialkylazodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656. The ether product 140.23 is then converted into theketodiol 140.24.

Using the above procedures, but employing, in place of the hydroxylamine140.20, different hydroxy-substituted hydroxylamines, and/or differenthydroxy-substituted aryl phosphonates, the products analogous to 140.24are obtained.

EXAMPLE 141 Preparation of Representative Prednisone Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illustrated above. In this procedure, the BMD-protected dienone139.2 is reduced to afford the 1,2-dihydro product 141.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product 141.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 141.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles141.4 and 141.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles141.4 and 141.5 are then transformed via the BMD-protected intermediates141.6 and 141.7, into the phosphonates 141.8 and 141.9.

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl ring and an ester or an amide linkage is illustratedabove. In this procedure, the ketoaldehyde 141.2 is reacted, asdescribed above, with 3-carboxyphenylhydrazine 141.10 (Apin) to give thepyrazoles 141.11 and 141.12. The 2′-substituted isomer 141.11 is thenreacted in dichloromethane solution at ambient temperature with onemolar equivalent of a dialkyl 2-hydroxy-2-methylpropyl phosphonate141.13 (FR 2462440) and dicyclohexylcarbodiimide, to yield the ester141.14. The protecting groups are then removed to yield the diol 141.15.

Alternatively, the 1′-substituted pyrazole 141.12 is coupled with adialkyl 2-aminoethyl phosphonate 141.17 (Aurora) to afford the amide141.18. The preparation of amides from carboxylic acids and derivativesis described, for example, in Organic Functional Group Preparations, byS. R. Sandler and W. Karo, Academic Press, 1968, p. 274, andComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.972ff. The carboxylic acid is reacted with the amine in the presence ofan activating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide. The conversion of a carboxylic acid into thecorresponding acid chloride can be effected by treatment of thecarboxylic acid with a reagent such as, for example, thionyl chloride oroxalyl chloride in an inert organic solvent such as dichloromethane,optionally in the presence of a catalytic amount of dimethylformamide.The product 141.18 is then deprotected to give the diol 141.19.

Using the above procedures, but employing different amino orhydroxyl-substituted phosphonates, and/or different carboxy-substitutedhydrazines, the products analogous to 141.15 and 141.19 are obtained.The functionalization procedures are typically interchangeable betweenthe pyrazole substrates 141.11 and 141.12.

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl group and an alkoxy or alkylthio carbonchain is illustrated above. In this procedure, the ketoaldehyde 141.2 isreacted, as described above, with 4-hydroxyphenyl hydrazine 141.20 (EP437105) to produce the pyrazoles 141.21 and 141.22. The 1′-substitutedisomer 141.21 is reacted, in dimethylformamide solution at 70°, with adialkyl bromopropyl phosphonate 141.23 (J. Amer. Chem. Soc., 2000, 122,1554) and potassium carbonate, to give the phosphonate 141.24. Theproduct is then deprotected to afford the diol 141.25.

Alternatively, the 2′-substituted pyrazole 141.22 is reacted in aMitsonobu reaction, as described above, with a dialkyl mercaptoethylphosphonate 141.26 (Zh. Obschei. Khim., 1973, 43, 2364) to prepare thethioether phosphonate 141.27 which is deprotected to give the diol141.28.

Using the above procedures, but employing, in place of the hydroxyphenylreagent 141.20, different hydroxy-substituted aralkyl, aryl orheteroaryl alkoxy hydrazines, and/or different dialkyl bromo ormercapto-substituted phosphonates, the products analogous to thecompounds 141.25 and 141.28 are obtained.

EXAMPLE 142 Preparation of Representative Prednisone Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde 141.2 is reacted with hydrazine toafford the pyrazole derivative 142.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 142.2, in which R² and X are as defined above, to yield thealkylation products 142.3 and 142.4. The alkylation of substitutedpyrazoles is described, for example, in Heterocyclic Chemistry, by T. L.Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 142.3 and 142.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 142.5 and 142.6, usingthe procedures described herein, and deprotection then affords the diols142.7 and 142.8.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 142.1 is reacted with one molar equivalent of adialkyl trifluoromethanesulfonyloxy phosphonate 142.9 to give thealkylated pyrazoles 142.10 and 142.11. Deprotection then yields thediols 142.12 and 142.13.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 142.1 is reacted, as described above, with1,4-bis(bromomethyl)Cyclohexane 142.14 (Salor) to give the pyrazoles142.15 and 142.16. The product 142.15 is subjected to an Arbuzovreaction, in which the bromomethyl substituent is converted into thedialkyl phosphonomethyl substituent, by reaction with a trialkylphosphite at 120°, to prepare, after deprotection of the side chain, thephosphonate 142.17. The pyrazole 142.16 is reacted in dimethylformamideat 70′ with potassium carbonate and a dialkyl aminomethyl phosphonate142.18 (Interchim) to give after deprotection the amino phosphonate142.19.

Using the above procedures, but employing, in place of the dibromide142.14, different dibromides, and/or different amino-substitutedphosphonates, the products analogous to 142.17 and 142.19 are obtained.

EXAMPLES 143-146 Clobetasol Derivatives

The structures of clobetasol (U.S. Pat. No. 3,721,687) andrepresentative phosphonate esters of the invention are shown below, inwhich the substituent R¹ is H, alkyl, alkenyl, aryl or aralkyl. Thesecompounds incorporate a phosphonate moiety (R¹O)₂P(O) connected to thenucleus by means of a variable linking group, designated as “link” inthe attached structures.

The synthesis of representative phosphonate derivatives of clobetasol isoutlined in Examples 143-146. In these Examples, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 143 Preparation of Representative Clobetasol Derivatives

The preparation of representative compounds of the invention isillustrated above. The steroid side-chain is protected as abis-methylenedioxy (BMD) moiety. In this sequence,9α-fluoro-16β-methyl-11β,17α21-trihydroxypregn-1,4-dien-3,21-dione 143.1(U.S. Pat. No. 3,721,687) is reacted with paraformaldehyde and an acidcatalyst such as hydrochloric acid, as described in Protective Groups inOrganic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, SecondEdition 1990, p. 223, to yield the BMD derivative 143.2. The phosphonatemoiety is then introduced, using the procedures described below, toproduce the phosphonate ester 143.3. The BMD moiety is then hydrolyzed,for example by treatment with 50% aqueous acetic acid, as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the triol 143.4. The21-hydroxy group is then converted into the 21-chloro group as describedin U.S. Pat. No. 3,721,687, Chimia, 1992, 46, 338, or J. Med. Chem.,1987, 30, 1581. In this procedure, the 21-hydroxy substrate is reactedat about 0° with one molar equivalent of methanesulfonyl chloride in abasic solvent such as pyridine, to afford the 21-mesylate 143.5. Theproduct is then reacted, in dimethylformamide solution at about 70°,with ca. five molar equivalents of lithium chloride, to yield the21-chloro product 143.6.

EXAMPLE 144 Preparation of Representative Clobetasol Derivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the BMD-protected derivative 143.2is reacted with an amine or hydroxylamine 144.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 1978, 86, 133. and in J. Mass. Spectrom., 1995, 30, 497. TheBMD-protected side-chain compound 144.2 is then converted into the triol144.3a, and then to the 21-chloro product 144.3b.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 144.4,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 144.5(Aldrich) to produce the ether 144.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 144.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 143.2 is reacted with a dialkyl phosphonomethyl hydroxylamine144.8, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime 144.9. Deprotectionthen affords the triol 144.10a from which the 21-chloro compound 144.10bis prepared. The oxime forming reaction is performed at ambienttemperature in ethanol-acetic acid solution between equimolar amounts ofthe reactants. Using the above procedures, but employing, in place ofthe hydroxylamine ether 144.8, different oxime ethers 144.1, thecorresponding products 144.3b are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a 3-pyridylmethoxy oxime group is illustrated above. In thisprocedure, the dienone 143.2 is reacted, as described above, withO-(5-bromo-3-pyridylmethoxy)hydroxylamine 144.11, prepared as describedabove from 5-bromo-3-bromomethylpyridine (WO 9528400) and BOC-protectedhydroxylamine, to give, after deprotection of the side-chain, the oxime144.12. The product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphite 144.13 to afford the phosphonate144.14a. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem., 35, 1371, 1992. The reaction is performed in an inertsolvent such as toluene, in the presence of a base such as triethylamineand a catalytic amount of tetrakis(triphenylphosphine)-palladium(0). The21-hydroxy group is then converted into the 21-chloro derivative144.14b.

Alternatively, the bromo compound 144.12 is coupled with a dialkyl4-vinylphenyl phosphonate 144.15 (Macromolecules, 1998, 31, 2918) toafford the phosphonate 144.16a. The coupling of aryl halides witholefins by means of the Heck reaction is described, for example, inAdvanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum,2001, p. 503ff and in Acc. Chem. Res., 12, 146, 1979. The aryl bromideand the olefin are coupled in a polar solvent such as dimethylformamideor dioxan, in the presence of a palladium(0) catalyst such astetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst suchas palladium(II) acetate, and optionally in the presence of a base suchas triethylamine or potassium carbonate. Optionally, the styrenoiddouble bond present in the product 144.16a is reduced, for example byreaction with diimide, to produce the saturated analog 144.17a. Thereduction of olefinic bonds is described in Comprehensive OrganicTransformations, by R. C. Larock, VCH, 1989, p. 6ff. The transformationis effected by means of catalytic hydrogenation, for example using apalladium on carbon catalyst and hydrogen or a hydrogen donor, or by theuse of diimide or diborane. The products 144.16a and 144.17a are thenconverted into the 21-chloro analogs 144.16b and 144.17b.

Using the above procedures, but employing, in place of thebromopyridylmethoxy reagent 144.11, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 144.14b, 144.16band 144.17b are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate 143.2 is reacted with a dialkyl 4-aminobenzyl phosphonate144.18, (Fluka) to give, after deprotection, the imine product 144.19a.The reaction is conducted in a hydrocarbon solvent such as toluene orxylene, at reflux temperature, in the presence of a basic catalyst suchas sodium methoxide, or an acid catalyst such as p-toluenesulfonic acid,under azeotropic conditions. The product is then converted into the21-chloro compound 144.19b. Using the above procedures, but employing,in place of the 4-aminobenzyl phosphonate 144.18 differentamino-substituted aryl or heteroaryl phosphonates, products analogous to144.19b are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and a thioether linkage is illustrated above.In this procedure, the dienone 143.2 is reacted withO-(2-mercaptoethyl)hydroxylamine 144.20 (Bioorganicheskaya Khim., 1986,12, 1662) to yield the oxime 144.21. The reaction of steroidal1,4-dien-3-ones with substituted hydroxylamines is described in J.Steroid Bioch., 1976, 7, 795; the reaction is performed betweenequimolar amounts of the reactants in a polar organic solvent such aspyridine or methanol, optionally in the presence of acetic acid orsodium acetate. The product is then coupled, in a Mitsonobu reaction,with a dialkyl 3-hydroxyphenyl phosphonate 144.22 (Aurora), to yield thethioether oxime 144.23. The preparation of aromatic ethers by means ofthe Mitsonobu reaction is described, for example, in ComprehensiveOrganic Transformations, by R. C. Larock, VCH, 1989, p. 448, and inAdvanced Organic Chemistry, Part B, by F. A. Carey and R. J. Sundberg,Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335. The phenol andthe alcohol or thiol component are reacted together in an aproticsolvent such as, for example, tetrahydrofuran, in the presence of adialkyl azodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656. The thioether product 144.23 is then converted intothe 21-chloro product 144.24b.

Using the above procedures, but employing, in place of the hydroxylamine144.22, different hydroxy or mercapto-substituted hydroxylamines, and/ordifferent hydroxyaryl-substituted phosphonates, the products analogousto 144.24b are obtained.

EXAMPLE 145 Preparation of Representative Clobetasol Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illustrated above. In this procedure, the BMD-protected dienone143.2 is reduced to afford the 1,2-dihydro product 145.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product 145.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 145.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles145.4 and 145.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles145.4 and 145.5 are then transformed, via the BMD-protectedintermediates 145.6 and 145.7, into the 21-chloro phosphonates 145.8band 145.9b.

The preparation of phosphonates in which the phosphonate is attached bymeans of a carbamate or an amino linkage is illustrated above. In thisprocedure, the ketoaldehyde 145.2 is reacted, as described above, with3-aminophenyl-hydrazine 145.10 (EP 437105) to give the pyrazoles 145.11and 145.12. The 2′-substituted isomer 145.11 is then reacted indimethylformamide solution at ambient temperature with one molarequivalent of a dialkyl 2-hydroxyethyl phosphonate 145.13 (Epsilon) andcarbonyl diimidazole, to yield the carbamate 145.14. The preparation ofcarbamates is described in Comprehensive Organic Functional GroupTransformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p 416ff,and in Organic Functional Group Preparations, by S. R. Sandler and W.Karo, Academic Press, 1986, p. 260ff. In the procedure, the amine isreacted in an inert aprotic solvent such as dichloromethane ortetrahydroftiran, with phosgene or a functional equivalent thereof, suchas carbonyl diimidazole, triphosgene, pentafluorophenyl carbonate andthe like, to afford the corresponding activated acylamine. The lattercompound is then reacted with an alcohol to yield the carbamate. The BMDprotecting group is then removed and the product is converted into the21-chloro product 145.16b.

Alternatively, the 1′-substituted pyrazole 145.12 is reacted, in areductive amination reaction, with a dialkyl formylmethyl phosphonate145.17 (Zh. Obschei. Khim., 1987, 57, 2793) and sodiumtriacetoxyborohydride, to afford the amine 145.18. The preparation ofamines by means of reductive amination procedures is described, forexample, in Comprehensive Organic Transformations, by R. C. Larock, VCH,p 421, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R.J. Sundberg, Plenum, 2001, p 269. In this procedure, the amine componentand the aldehyde or ketone component are reacted together in thepresence of a reducing agent such as, for example, borane, sodiumcyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminumhydride, optionally in the presence of a Lewis acid, such as titaniumtetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990. Theproduct 145.18 is then deprotected to give the triol 145.19a, and thelatter compound is transformed into the 21-chloro analog 145.19b.

Using the above procedures, but employing different formyl orhydroxyl-substituted phosphonates, and/or different amino-substitutedhydrazines, the products analogous to 145.16b and 145.19b are obtained.The functionalization procedures are typically interchangeable betweenthe pyrazole substrates 145.11 and 145.12.

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl ring and an amide linkage is illustratedabove. In this procedure, the ketoaldehyde 145.2 is reacted, asdescribed above, with 3-carboxyphenyl hydrazine 145.20 (Apin) to producethe pyrazoles 145.21 and 145.22. The 1′-substituted isomer 145.21 iscoupled, in the presence of dicyclohexylcarbodiimide, with a dialkyl3-aminophenyl phosphonate 145.23 (Aurora) to give the amide 145.24. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in Organic Functional Group Preparations, by S.R. Sandler and W. Karo, Academic Press, 1968, p. 274, and ComprehensiveOrganic Transformations, by R. C. Larock, VCH, 1989, p. 972ff. Thecarboxylic acid is reacted with the amine in the presence of anactivating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide. The product is then deprotectedto afford the triol 145.25a which is converted into the 21-chlorocompound 145.25b.

Alternatively, the 2′-substituted pyrazole 145.22 is coupled, asdescribed above, with a dialkyl methylaminomethyl phosphonate 145.26(AsInEx) to prepare the amide phosphonate 145.27 which is deprotected,and the product is converted into the 21-chloro analog 145.28b.

Using the above procedures, but employing, in place of the carboxyphenylhydrazine 145.20, different carboxy-substituted aralkyl, aryl orheteroaryl alkoxy hydrazines, and/or different dialkyl amino-substitutedphosphonates, the products analogous to the compounds 145.25b and145.28b are obtained.

EXAMPLE 146 Preparation of Representative Clobetasol Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde 145.2 is reacted with hydrazine, toafford the pyrazole derivative 146.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 146.2, in which R² and X are as defined above, to yield thealkylation products 146.3 and 146.4. The alkylation of substitutedpyrazoles is described, for example, in Heterocyclic Chemistry, by T. L.Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 146.3 and 146.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 146.5 and 146.6, usingthe procedures described herein, and deprotection/acylation then affordsthe 21-chloro compounds 146.7b and 146.8b.

The preparation of representative compounds of the invention isillustrated above. The pyrazole 146.1 is reacted in tetrahydrofuransolution, as described above, with one molar equivalent of a dialkylbromobutenyl phosphonate 146.9 (J. Med. Chem., 1992, 35, 1371) andlithium hexamethyldisilazide to give the alkylated pyrazoles 146.10 and146.11. Deprotection/chlorination then yields the 21-chloro products146.12b and 146.13b.

The preparation of representative compounds of the invention isillustrated above. The pyrazole 146.1 is reacted in tetrahydrofuransolution, as described above, with 1,4-dibromobut-2-yne 146.14 (Aldrich)to give the pyrazoles 146.15 and 146.16. The products are subjected toan Arbuzov reaction, in which the bromomethyl substituent is convertedinto the dialkyl phosphonomethyl substituent, by reaction with atrialkyl phosphite at 1200, to prepare, after deprotection of the sidechain and chlorination, the 21-chloro phosphonates 146.17b and 146.18b.The Arbuzov reaction is described in Handb. Organophosphorus Chem.,1992, 115-72. In the procedure, the substrate is heated at from 60° toabout 160° with a five to fifty-fold molar excess of the trialkylphosphite. Using the above procedures, but employing, in place of thedibromide 146.14, different dibromides, the products analogous to146.17b and 146.18b are obtained.

EXAMPLE 147 Preparation of Representative Compounds of Formulae 148 and149

Representative compounds of the invention can be prepared as generallydescribed by Westwood et al, J. Med. Chem., 1996, 39, 4608-4621, andaccording to the following general route.

Coupling of a suitable aniline 147.1 wherein X¹ is hydrogen, halo,trifluoromethyl, (C₁-C₃)alkyl, cyano, or (C₁-C₃)alkoxy, with acidchloride 147.2 provides a representative compound of Formula 148 or 149.

EXAMPLE 148 Synthesis of Representative Compounds of Formulae 150-153

Compounds of the invention can be prepared as generally illustratedabove. A β-ketonitrile is generated from a phenylacetic acid bycondensation with a malononitrile ester under Claisen conditions.Reaction with hydroxylamine provides the 5-amino-1,2-oxazole which, uponcondensation with cyanomorpholine provides a SMP-114 analog of theinvention.

The prepration of suitable carboxylic acid intermediates that can beincorporated into the above synthetic scheme is detailed below.

The anisole derivative is demethylated by treatment with a Lewis acidsuch as boron tribromide. The resulting phenol is alkylated withE-1,4-dibromobutene and the resulting monobromide is heated withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., Synthesis of carbon-phosphorusbonds, CRC press, 1988) to generate the diethyl ester of the desiredphosphonic acid. Saponification of the carboxylate ester gives thephenylacetic acid ready for incorporation into the synthesis of SMP-114analogs.

Using a procedure silimar to that described above, except replacingE-1,4-dibromobutene with 1,3-dibromopropane, a suitable intermediate canbe prepared.

The free phenol in ethyl homovanillate is converted to the aryltriflate, and the biphenyl motif is generated by Suzuki coupling withphenylboronic acid (see Chem. Rev., 1995, 95, 2457). The remaining stepsare analogous to those described immediately above.

Ethyl 4-bromophenylacetate is coupled with 4-methoxyphenylboronic acidusing the Suzuki method. The remaining steps are analogous to thosedescribed above.

EXAMPLE 149 Synthesis of Representative Compounds of Formulae 154-155

Compounds of the invention can be prepared as generally described byWestwood et al, J. Med. Chem., 1996, 39, 4608-4621, according to thegeneral route outline below.

Coupling of a suitable aniline wherein X is hydrogen, halo,trifluoromethyl, cyano, or methyl with acid chloride followed bytreatment with sodium ethoxide provides a representative compounds ofFormulae 154 and 155.

EXAMPLE 150 Synthesis of Representative Compounds of Formulae 156

Representative compounds of the invention can generally be prepared asillustrated above.

Certain specific salicylic acid analogs of the invention can be preparedas illustrated above. Salicylic acid is converted to its acid chlorideby treatment with oxalyl chloride in dimethylformamide. The acidchloride is then coupled with 2-aminoethylphosphonic acid diethyl esterin the presence of a base such as triethylamine in a solvent such asdichloromethane to generate the desired amide product.

2-Aminophenol is acylated with an activated diethylphosphonoacetic acidto provide the desired amide linker compound, according to a proceduresuch as those reported in J. Med. Chem., 1982, 25, 960-964 and J. Med.Chem., 1984, 27, 600-604. The activated diethylphosphonoacetic acid isobtained by treatment in a solvent such as dimethylformamide with acoupling reagent such as diethyl cyanophosphonate and a base such asdiisopropylethylamine at room temperature.

2-Bromoaniline is coupled with pent-4-ynyl-phosphonic acid diethyl ester(generated from 5-chloro-1-pentyne and triethylphosphite in a solventsuch as toluene, or other Arbuzov reaction conditions: see Engel, R.,Synthesis of carbon-phosphorus bonds, CRC press, 1988) under conditionssuch as those pioneered by Sonagashira (Sonogashira, K.; Tohda, Y.;Hagihara, N. Tetrahedron Lett., 1975, 4467) to afford the desiredsalicylic acid analog containing a phosphonate.

EXAMPLE 151 Synthesis of Representative Compounds of Formulae 157

Compounds of the invention can generally be prepared as illustratedabove. For example, a specific compound of the invention can be preparedas follows.

The methyl ester shown is treated in a solvent such as ethanol withexcess E-1,4-dibromobutene in the presence of a base such as sodiumhydroxide, as described in J. Med. Chem., 1997, 40, 980. The monobromideso formed is then heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., Synthesisof carbon-phosphorus bonds, CRC press, 1988) to generate the diethylester of the desired phosphonic acid. Finally, heating with2-aminothiazole in solvents such as xylenes, as described in J. Med.Chem., 1997, 40, 980, gives the desired meloxicam analogue.

EXAMPLE 152 Synthesis of Representative Compounds of Formulae 158

Compounds of the invention can generally be prepared as illustratedabove. For example, a specific compound of the invention can be preparedas follows.

Rofecoxib is treated in a solvent such as dimethylformamide ortetrahydrofuran with a base such as sodium hydride. When bubblingceases, E-1,4-dibromobutene is added in excess. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the mono-alkylated product isisolated by chromatography. The bromide so formed is heated withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., Synthesis of carbon-phosphorusbonds, CRC press, 1988) to generate the diethyl ester of the desiredphosphonic acid.

EXAMPLE 153 Synthesis of Representative Compounds of Formulae 159

Compounds of the invention can generally be prepared as illustratedabove (see also, Ind. J. Chem., Sect B, 1990, 10, 954.) A specificintermediate useful in the above process can be prepared as follows.

Ethyl 4-hydroxyphenylacetate is treated in a solvent such asdimethylformamide or tetrahydrofuran with a base such as sodium hydride.When bubbling ceases, E-1,4-dibromobutene is added in excess. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, themono-alkylated product is isolated by chromatography. The bromide soformed is heated with triethylphosphite in a solvent such as toluene (orother Arbuzov reaction conditions: see Engel, R., Synthesis ofcarbon-phosphorus bonds, CRC press, 1988) to generate the diethyl esterof the desired phosphonic acid.

EXAMPLE 154 Synthesis of Representative Compounds of Formulae 160

Compounds of the invention can generally be prepared as illustratedabove. For example, a specific compound of the invention can be preparedas follows.

Etoricoxib is treated in a solvent such as dimethylformamide ortetrahydrofuran with a base such as sodium hydride. When bubblingceases, E-1,4-dibromobutene is added in excess. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the mono-alkylated product isisolated by chromatography. The bromide so formed is heated withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., Synthesis of carbon-phosphorusbonds, CRC press, 1988) to generate the diethyl ester of the desiredphosphonic acid.

EXAMPLE 155 Synthesis of Representative Compounds of Formulae 161

Compounds of the invention can generally be prepared as illustratedabove. Acylation is achieved by reaction of the sulfonamide with anactivated diethylphosphonoacetic acid to provide the desired compound,according to a procedure such as those reported in J. Med. Chem., 1982,25, 960 and J. Med. Chem., 1984, 27, 600. The activateddiethylphosphonoacetic acid can be obtained by treatment in a solventsuch as dimethylformamide with a coupling reagent such as diethylcyanophosphonate and a base such as diisopropylethylamine at roomtemperature. For example, a specific compound of the invention can beprepared as follows.

Acylation is achieved by reaction of the sulfonamide with an activateddiethylphosphonoacetic acid to provide the desired compound, accordingto a procedure such as those reported in J. Med. Chem., 1982, 25, 960and J. Med. Chem., 1984, 27, 600. The activated diethylphosphonoaceticacid can be obtained by treatment in a solvent such as dimethylformamidewith a coupling reagent such as diethyl cyanophosphonate and a base suchas diisopropylethylamine at room temperature.

EXAMPLE 156 Synthesis of Representative Compounds of Formulae 162

Compounds of the invention can generally be prepared as illustratedabove. The synthesis of celecoxib analogs from a number of acetophenonesis described in detail in J. Med. Chem., 1997, 40, 1347. The synthesisof a suitable phosphonate-containing acetophenone is illustrated below.

5-Chloro-1-pentyne is treated with triethylphosphite in a solvent suchas toluene (or other Arbuzov reaction conditions: see Engel, R.,Synthesis of carbon-phosphorus bonds, CRC press, 1988) to generate thediethyl ester of the desired phosphonic acid. This acetylene is coupledwith 3′-bromo-4-methylacetophenone under conditions such as thosepioneered by Sonagashira (Sonogashira, K.; Tohda, Y.; Hagihara, N.Tetrahedron Lett., 1975, 4467).

EXAMPLE 157 Synthesis of Representative Compounds of Formulae 163

Compounds of the invention can generally be prepared as illustratedabove. The synthesis of celecoxib analogs from a number of acetophenonesis described in detail in J. Med. Chem., 1997, 40, 1347. The synthesisof a suitable acetophenone linked at the 4′ position to a phosphonatemoiety is illustrated below.

4′-Hydroxyacetophenone is treated in a solvent such as dimethylformamideor tetrahydrofuran with a base such as sodium hydride. When bubblingceases, E-1,4-dibromobutene is added in excess. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the mono-alkylated product isisolated by chromatography. The bromide so formed is heated withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., Synthesis of carbon-phosphorusbonds, CRC press, 1988) to generate the diethyl ester of the desiredphosphonic acid.

EXAMPLES 158-161 Preparation of Halobetasol Derivatives

The synthesis of representative phosphonate derivatives of halobetasolis outlined in Examples 158-161. In these Examples, it may be necessaryto protect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 158 Preparation of Representative Halobetasol Derivatives

The preparation of representative compounds of the invention isillustrated above. The steroid side-chain is protected as abis-methylenedioxy (BMD) moiety. In this sequence,6α,9α-difluoro-16β-methyl-11β,17α,21-trihydroxypregn-1,4-dien-3,21-dione158.1 (U.S. Pat. No. 4,619,921) is reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in ProtectiveGroups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative 158.2. Thephosphonate moiety is then introduced, using the procedures describedbelow, to produce the phosphonate ester 158.3. The BMD moiety is thenhydrolyzed, for example by treatment with 50% aqueous acetic acid, asdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to afford the triol158.4. The latter compound is then converted into the 17,21-cyclicorthoester 158.5 using the procedure described in Chem. Pharm. Bull.,1986, 34, 1613. The substrate is reacted in dimethylformamide at 70° C.with two molar equivalents of triethyl orthopropionate and a catalyticamount of p-toluenesulfonic acid. The product is then reacted with anexcess of trimethylsilyl chloride in dimethylformamide at ambienttemperature to produce the 21-chloro 17-propionate product 158.6.

Alternatively, the substrate 158.4 is converted into the product 158.6by means of the method described in J. Med. Chem., (1987), 30: 1581. Inthis procedure, the 21-hydroxy group is activated by conversion to the21-mesylate, by reaction with mesyl chloride in pyridine; the mesylategroup is then displaced to yield the 21-chloro intermediate, by reactionwith lithium chloride in dimethylformamide, and the 17-hydroxyl group isesterified to give the 21-chloro-17-propionate derivative 158.6. Theselective acylation of the 17α hydroxyl group in the presence of an 11βhydroxyl group is described in J. Med. Chem., (1987), 30: 1581.

EXAMPLE 159 Preparation of Representative Halobetasol Derivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the BMD-protected derivative 158.2is reacted with an amine or hydroxylamine 159.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., (1978), 86, 133. and in J. Mass. Spectrom., (1995), 30, 497. TheBMD-protectedside-chain compound 159.2 is then converted into the triol159.3a, and then to the 21-chloro 17 propionate product 159.3b.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 159.4,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 159.5(Aldrich) to produce the ether 159.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 159.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 158.2 is reacted with a dialkyl phosphonomethyl hydroxylamine159.8, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett. 27:1477 (1986))and BOC-hydroxylamine, to afford the oxime 159.9. Deprotection thenaffords the triol 159.10a from which the 21-chloro 17-propionatecompound 159.10b is prepared. The oxime forming reaction is performed atambient temperature in ethanol-acetic acid solution between equimolaramounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 159.8, different oxime ethers 159.1, the corresponding products159.3b are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a thienylmethoxy oxime group is illustrated above. In thisprocedure, the dienone 158.2 is reacted, as described above, withO-(4-bromo-2-thienylmethoxy)hydroxylamine 159.11, prepared as describedabove from 4-bromo-2-bromomethylthiophene (WO 9420456) and BOC-protectedhydroxylamine, to give, after deprotection of the side-chain, the oxime159.12. The product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphite 159.13 to afford the phosphonate159.14a. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem. 35:1371 (1992). The reaction is performed in an inert solventsuch as toluene, in the presence of a base such as triethylamine and acatalytic amount of tetrakis(triphenylphosphine)-palladium(0). The21-hydroxy compound 159.14a is then converted into the 21-chloro17-propionate derivative 159.14b.

Alternatively, the bromo compound 159.12 is coupled with a dialkylbutenyl phosphonate 159.15 (Org. Lett. 3:217 (2001)) to afford thephosphonate 159.16a. The coupling of aryl halides with olefins by meansof the Heck reaction is described, for example, in F. A. Carey and R. J.Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and in Acc.Chem. Res. 12:146 (1979). The aryl bromide and the olefin are coupled ina polar solvent such as dimethylformamide or dioxan, in the presence ofa palladium(0) catalyst such astetrakis(triphenyl-phosphine)palladium(0) or palladium(II) catalyst suchas palladium(II) acetate, and optionally in the presence of a base suchas triethylamine or potassium carbonate. Optionally, the double bondpresent in the product 159.16a is reduced, for example by reaction withdiimide, to produce the saturated analog 159.17a. The reduction ofolefinic bonds is described in R. C. Larock, Comprehensive OrganicTransformations 6ff (VCH 1989). The transformation is effected by meansof catalytic hydrogenation, for example using a palladium on carboncatalyst and hydrogen or a hydrogen donor, or by the use of diimide ordiborane. The products 159.16a and 159.17a are then converted into the21-chloro 17-propionate analogs 159.16b and 159.17b.

Using the above procedures, but employing, in place of thebromothienylmethoxy reagent 159.11, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 159.14b, 159.16band 159.17b are obtained.

The preparation of representative phosphonates of the invention isillustrated above. In this procedure, the substrate 158.2 is reactedwith a dialkyl 4-amino-2-thienyl phosphonate 159.18, prepared by thepalladium-catalyzed coupling, as described above, between4-amino-2-bromothiophene (Tet. 43:3295 (1987)) and a dialkyl phosphite,to give, after deprotection, the imine product 159.19a. The imineforming reaction is conducted in a hydrocarbon solvent such as tolueneor xylene, at reflux temperature, in the presence of a basic catalystsuch as sodium methoxide, or an acid catalyst such as p-toluenesulfonicacid, under azeotropic conditions. The product is then converted intothe 21-chloro 17-propionate compound 159.19b.

Using the above procedures, but employing, in place of the4-aminothienyl phosphonate 159.18 different amino-substituted aryl orheteroaryl phosphonates, products analogous to 159.19b are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an amide linkage is illustrated above. Inthis procedure, the dienone 158.2 is reacted withO-(4-aminobutyl)hydroxylamine 159.20 (Pol. J. Chem. 55:1163 (1981)) toyield the oxime 159.21. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch. 7:795(1976); the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The productis then coupled with a dialkyl 2-hydroxyethyl phosphonate 159.22(Epsilon) and carbonyl diimidazole, to yield the carbamate oxime 159.23.The preparation of carbamates is described in A. R. Katritzky,Comprehensive Organic Functional Group Transformations, 6:416ff(Pergamon, 1995), and in S. R. Sandler and W. Karo, Organic FunctionalGroup Preparations, 260ff (Academic Press, 1986). In the procedure, theamine is reacted in an inert aprotic solvent such as dichloromethane ortetrahydrofuran, with phosgene or a functional equivalent thereof, suchas carbonyl diimidazole, triphosgene, pentafluorophenyl carbonate andthe like, to afford the corresponding activated acylamine. The lattercompound is then reacted with an alcohol to yield the carbamate. Thecarbamate product 159.23 is then converted into the 21-chloro17-propionate product 159.24b.

Using the above procedures, but employing, in place of the hydroxylamine159.22, different amino-substituted hydroxylamines, and/or differenthydroxy-substituted phosphonates, the products analogous to 159.24b areobtained.

EXAMPLE 160 Preparation of Representative Halobetasol Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and/or a variablecarbon chain is illustrated above. In this procedure, the BMD-protecteddienone 158.2 is reduced to afford the 1,2-dihydro product 160.1. Thecatalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem. 44:602 (2001). The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc. 86:1520(1964), to afford the 2-formyl product 160.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 160.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles160.4 and 160.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc. 86:1520 (1964). The pyrazoles160.4 and 160.5 are then transformed via the BMD-protected intermediates160.6 and 160.7, into the 21-chloro 17-propionate phosphonates 160.8band 160.9b.

The preparation of phosphonates in which the phosphonate is attached bymeans of an amide linkage is illustrated above. In this procedure, theketoaldehyde 160.2 is reacted, as described above, with 3-carboxypropylhydrazine 160.10 (Ind. J. Exp. Biol. 32:218 (1994)) to give thepyrazoles 160.11 and 160.12. The 2′-substituted isomer 160.11 is thenreacted in dimethylformamide solution at ambient temperature with onemolar equivalent of a dialkyl 4-aminophenyl phosphonate 160.13 (Epsilon)and dicyclohexyl carbodiimide, to yield the amide 160.14. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in S. R. Sandler and W. Karo, Organic FunctionalGroup Preparations, 274 (Academic Press, 1968), and R. C. Larock,Comprehensive Organic Transformations, 972ff (VCH, 1989). The carboxylicacid is reacted with the amine in the presence of an activating agent,such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The BMD protecting group is then removed and the product is convertedinto the 21-chloro 17-propionate product 160.16b.

Alternatively, the 1′-substituted pyrazole 160.12 is coupled, asdescribed above, with a dialkyl aminomethyl phosphonate 160.17(Interchim), to afford the amide 160.18. The product 160.18 is thendeprotected to give the triol 160.19a, and the latter compound istransformed into the 21-chloro 17-propionate 160.19b.

Using the above procedures, but employing different amino-substitutedphosphonates, and/or different carboxy-substituted hydrazines, theproducts analogous to 160.16b and 160.19b are obtained. Thefunctionalization procedures are interchangeable between the pyrazolesubstrates 160.11 and 160.12.

The preparation of the phosphonates in which the phosphonate group isattached by means of an aryl ring and a propenyl linkage is illustratedabove. In this procedure, the ketoaldehyde 160.2 is reacted, asdescribed above, with allyl hydrazine 160.20 (Zh. Org. Khim., 3:983(1967)) to produce the pyrazoles 160.21 and 160.22. The 1′-substitutedisomer 160.21 is coupled with a dialkyl 3-bromophenyl phosphonate 160.23(Epsilon) to give the phosphonate 160.24. The product is thendeprotected to afford the triol 160.25a which is converted into the21-chloro 17-propionate compound 160.25b.

Alternatively, the 2′-substituted pyrazole 160.22 is coupled, asdescribed above, with a dialkyl 5-bromo-2-thienyl phosphonate 160.26(Syn., 455 (2003)) to prepare the phosphonate 160.27 which isdeprotected, and the product is converted into the 21-chloro17-propionate analog 160.28b.

Using the above procedures, but employing, in place of the propenylhydrazine 160.20, different alkenyl hydrazines, and/or different dialkylbromo-substituted phosphonates, the products analogous to the compounds160.25b and 160.28b are obtained.

EXAMPLE 161 Preparation of Representative Halobetasol Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde 160.2 is reacted with hydrazine, toafford the pyrazole derivative 161.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,86:1520 (1964). The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 161.2, in which R² and X are as defined above, to yield thealkylation products 161.3 and 161.4. The alkylation of substitutedpyrazoles is described, for example, in T. L. Gilchrist, HeterocyclicChemistry, 309 (Longman, 1992). The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 161.3 and 161.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 161.5 and 161.6, usingthe procedures described herein, and deprotection/chlorination/acylationthen affords the 21-chloro 17-propionate compounds 161.7b and 161.8b.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 161.1 is reacted with 2-bromobenzyl bromide 161.9 togive the pyrazoles 161.10 and 161.11. The products are then coupled, asdescribed above, with a dialkyl phosphite, to afford after side-chaindeprotection and modification, as described above, the 21-chloro 17propionates 161.12b and 161.13b.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 161.1 is reacted in tetrahydrofuran solution, asdescribed above, with 4-bromomethyl cyclohexanone 161.14 (WO 9737959) togive the alkylation products 161.15 and 161.16. The 1′-substitutedisomer 161.15 is then reacted, in a reductive amination reaction, with adialkyl aminomethyl phosphonate (Interchim) and sodium cyanoborohydride,to yield, after deprotection and side-chain modification, the 21-chloro17-propionate 161.17b.

The preparation of amines by means of reductive amination procedures isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations, 421 (VCH, 1989), and in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B, 269 (Plenum, 2001). In thisprocedure, the amine component and the aldehyde or ketone component arereacted together in the presence of a reducing agent such as, forexample, borane, sodium cyanoborohydride, sodium triacetoxyborohydrideor diisobutylaluminum hydride, optionally in the presence of a Lewisacid, such as titanium tetraisopropoxide, as described in J. Org. Chem.,55:2552 (1990).

The 2′-substituted pyrazole 161.16 is subjected to the same series ofreaction to give the amine phosphonate 161.18b.

Using the above procedures, but employing differentbromomethyl-substituted aldehydes or ketones, and/or differentamino-substituted phosphonates, the products analogous to 161.17b and161.18b are obtained.

EXAMPLE 162 Synthesis of Representative Compounds of Formulae 164

Compounds of the invention can generally be prepared as illustratedabove. The chloride is made from(3,4-bis-difluoromethoxy-phenyl)-phenyl-methanone (cf U.S. Pat. No.5,622,977) by reduction with sodium borohydride in ethanol and treatmentof the resulting alcohol with triphenylphosphine, carbon tetrachlorideand diisopropyl azodicarboxylate in a solvent such as tetrahydrofuran.The condensation is achieved by treatment of the two reagents withsodium ethoxide in ethanol. The ethyl ester in the product is saponifiedby treatment with lithium hydroxide in ethanol, and the resulting acidis decarboxylated by heating under acidic conditions. The twoenantiomers of the product may be separated by chromatography.

For example, a specific pyridine reagent can be prepared as follows.

(2-Oxo-1,2-dihydro-pyridin-4-yl)-acetic acid ethyl ester is treated witha base such as sodium hydride in a solvent such as tetrahydrofuran.After bubbling ceases, an excess of 1,3-dibromopropane is added. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, the mono-bromideis isolated by chromatography. The bromide is then heated withtriethylphosphite in a solvent such as toluene to generate the diethylester of the desired phosphonic acid.

EXAMPLES 163-166 Ciclesonide Derivatives

The synthesis of representative phosphonate derivatives of ciclesonideis outlined in Examples 166-169. In these Examples, it may be necessaryto protect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 163 Preparation of Representative Ciclesonide Derivatives

Representative compounds of the invention can be pepared as follows.Ciclesonide 163.1 (U.S. Pat. No. 5,482,934) is protected to afford thederivative 163.2. The ketone is protected, for example, by conversion tothe cyclic ethylene ketal, by reaction in toluene solution at refluxtemperature with ethylene glycol and an acid catalyst, as described inJ. Am. Chem. Soc., 77:1904 (1955). Deprotection is effected by reactionwith pyridinium tosylate in aqueous acetone, as described in J. Chem.Soc. Chem. Comm. 1351 (1987).

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 163.1 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn. 50:102 (1970). The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc. 101:5841 (1979).

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 163.1 is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc. Chem. Comm. 406(1983), to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The protected compound 163.2 is then converted into thephosphonate-containing analog 163.3, using the procedures describedbelow, and the protecting group is then removed, as described above, togive the phosphonate 163.4.

EXAMPLE 164 Preparation of Representative Ciclesonide Derivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the protected derivative 164;1 isreacted with an amine or hydroxylamine 164.2, in which R² is an alkyl,alkenyl, cycloalkyl or cycloalkenyl group, optionally incorporating aheteroatom O, S or N, or a functional group such as an amide, ester,oxime, sulfoxide or sulfone etc, or an optionally substituted aryl,heteroaryl or aralkyl group, optionally incorporating a heteroatom O, Sor N, and X is either a phosphonate group or a group which issubsequently converted into a phosphonate-containing substituent. Forexample, X is dialkylphosphono, bromo, hydroxy, amino, carboxy and thelike. The reaction is conducted between equimolar amounts of thereactants in an aprotic solvent such as pyridine or xylene, or in analcoholic solvent such as ethanol, optionally in the presence of an acidcatalyst, to give the imine or oxime 164.3. The preparation of oximes ofsteroidal 3-ketones is described in Anal. Bioch. 86:133 (1978) and in J.Mass. Spectrom. 30:497 (1995). The protecting group is then removed toafford the 20-keto phosphonate product 164.4.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 164.5,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 164.6(Aldrich) to produce the ether 164.7. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 164.8. The above procedure is also employed for the preparation ofsubstituted hydroxylamines which are precursors to phosphonates.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 164.1, in which the 20-ketone is protected as the dimethylhydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine 164.8, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett. 27:1477(1986)) and BOC-hydroxylamine, to afford the oxime 164.10. Deprotectionaffords the 20-keto phosphonate 164.11. The oxime forming reaction isperformed at ambient temperature in ethanol-acetic acid solution betweenequimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 164.8, different oxime ethers 164.2, the corresponding products164.4 are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a benzyloxy oxime group is illustrated above. In thisprocedure, the dienone 164.1, in which the 20-ketone is protected as thedimethyl hydrazone, is reacted, as described above, withO-(4-bromobenzyloxy)hydroxylamine 164.9, prepared as described abovefrom 4-bromobenzyl bromide and BOC-protected hydroxylamine 164.6, togive the oxime 164.12. The protecting group is then removed to yield the20-keto product 164.13. The latter product is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphite 164.14 toafford the phosphonate 164.15. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem. 35:1371 (1992). The reaction isperformed at ca. 100° C. in an inert solvent such as toluene, in thepresence of a base such as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 164.13 is coupled with a dialkyl vinylphosphonate 164.16 (Aldrich) to afford the phosphonate 164.17. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res. 12:146(1979). The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 164.17 isreduced, for example by reaction with diimide, to produce the saturatedanalog 164.18. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromobenzyloxy reagent 164.9, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, products analogous to the compounds 164.15, 164.17 and164.18 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of a 3-furylimino group is illustrated above. In this procedure,the substrate 164.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with a dialkyl 4-amino-2-furyl phosphonate164.20, prepared by the palladium catalyzed coupling reaction, asdescribed above, between 4-amino-2-bromofuran (Tetrahedron Lett. 43:3295(1987)) and a dialkyl phosphite, to give, after deprotection, the imineproduct 164.21. The imine forming reaction is conducted in a hydrocarbonsolvent such as toluene or xylene, at reflux temperature, in thepresence of a basic catalyst such as sodium methoxide, or an acidcatalyst such as p-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the4-amino-2-furyl phosphonate 164.20 different amino-substituted aryl orheteroaryl phosphonates, products analogous to 164.21 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an amide linkage is illustrated above. Inthis procedure, the dienone 164.1, in which the 20-ketone is protectedas the dimethylhydrazone, is reacted withO-(2-carboxyethyl)hydroxylamine 164.22 (J. Med. Chem. 33:1423 (1990)) toyield the oxime 164.23. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch. 7:795(1976); the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The product164.23 is then coupled with a dialkyl 4-aminophenyl phosphonate 164.24(Epsilon) and dicyclohexylcarbodiimide, to yield, after deprotection theamide oxime 164.25. The preparation of amides from carboxylic acids andderivatives is described, for example, in S. R. Sandler and W. Karo,Organic Functional Group Preparations 274 (Academic Press, 1968) and R.C. Larock, Comprehensive Organic Transformations 972ff (VCH, 1989). Thecarboxylic acid is reacted with the amine in the presence of anactivating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

Using the above procedures, but employing, in place of thecarboxy-substituted hydroxylamine 164.22, different carboxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates,products analogous to 164.25 are obtained.

EXAMPLE 165 Preparation of Representative Ciclesonide Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and/or a variablecarbon chain is illusrated above. In this procedure, the dienone 163.1is reduced to afford the 1,2-dihydro product 165.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem. 44:602 (2001). The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc. 86:1520(1964), to afford the 2-formyl product 165.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 165.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles165.4 and 165.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc. 86:1520 (1964). The pyrazoles165.4 and 165.5 are then transformed into the phosphonates 165.6 and165.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of an alkoxy or alkylthio linkage is illustrated above. In thisprocedure, the ketoaldehyde 165.2 is reacted, as described above, with4-hydroxyphenyl hydrazine 165.8 (EP 437105) to give the pyrazoles 165.9and 165.10. The 2′-substituted isomer 165.9 is then reacted indimethylformamide solution at ca. 70° C. with a dialkyl bromobutenylphosphonate 165.11 (J. Med. Chem. 35:1371 (1992)) and potassiumcarbonate, to yield the ether phosphonate 165.12.

The isomeric pyrazole 165.10 is reacted, in a Mitsonobu reaction, with adialkyl mercaptomethyl phosphonate 165.13 (J. Med. Chem. 26:1688 (1985))to yield the thioether phosphonate 165.14. The preparation of aromaticethers and thioethers by means of the Mitsonobu reaction is described,for example, in R. C. Larock, Comprehensive Organic Transformations 448(VCH, 1989), in F. A. Carey and R. J. Sundberg, Advanced OrganicChemistry, Part B 153-4 (Plenum, 2001), and in Org. React. 42:335(1992). The phenol and the alcohol or thiol component are reactedtogether in an aprotic solvent such as, for example, tetrahydrofuran, inthe presence of a dialkyl azodicarboxylate and a triarylphosphine, toafford the ether or thioether products. The procedure is also describedin Org. React. 42:335-656 (1992).

Using the above procedures, but employing different hydroxy-substitutedhydrazines, and/or different bromo- or mercapto-substitutedphosphonates, products analogous to 165.12 and 165.14 are obtained.

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl group and an amide or carbamate linkage isillustrated above. In this procedure, the ketoaldehyde 165.2 is reacted,as described above, with 4-aminophenyl hydrazine 165.15 (Epsilon) toproduce the pyrazoles 165.16 and 165.17. The 2′-substituted isomer165.16 is coupled, as described above, with a dialkyl phosphonoaceticacid 165.18 (Aldrich) and dicyclohexyl carbodiimide, to give the amidephosphonate 165.19.

Alternatively, the 1′-substituted pyrazole 165.17 is reacted with adialkyl 3-hydroxypropyl phosphonate 165.20 (Zh. Obschei. Khim. 43:2364(1973)), and carbonyl diimidazole to prepare the carbamate phosphonate165.21. The preparation of carbamates is described in ComprehensiveOrganic Functional Group Transformations Vol. 6 416ff (A. R. Katritzky,ed., Pergamon, 1995) and in S. R. Sandler and W. Karo, OrganicFunctional Group Preparations 260ff (Academic Press, 1986). In theprocedure, the amine is reacted in an inert aprotic solvent such asdichloromethane or tetrahydrofuran, with phosgene or a functionalequivalent thereof, such as carbonyl diimidazole, triphosgene,pentafluorophenyl carbonate and the like, to afford the correspondingactivated acylamine. The latter compound is then reacted with an alcoholto yield the carbamate.

Using the above procedures, but employing, in place of the 4-aminophenylhydrazine 165.15, different amino-substituted hydrazines, and/ordifferent dialkyl carboxy or hydroxy-substituted phosphonates, productsanalogous to the compounds 165.19 and 165.21 are obtained.

EXAMPLE 166 Preparation of Representative Ciclesonide Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde 165.2 is reacted with hydrazine, toafford the pyrazole derivative 166.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc.86:1520 (1964). The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 166.2, in which R² and X are as defined above, or a reactivebromoheteroaromatic reagent, to yield the alkylation products 166.3 and166.4. The alkylation of substituted pyrazoles is described, forexample, in T. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992).The reaction is performed between equimolar amounts of the substrates ina polar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as dimethylaminopyridine, lithiumhexamethyldisilazide and the like. The products 166.3 and 166.4 are,except in cases where X is dialkylphosphono, converted into thephosphonates 166.5 and 166.6, using the procedures described herein.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 166.1 is reacted, as described above, with a dialkylacetonyl phosphonate 166.7 (Tetrehedron Lett. 34:649 (1978)) to give thepyrazoles 166.8 and 166.9.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 166.1 is reacted in tetrahydrofuran solution, with2,5-bis(bromomethyl)thiophene 166.10 (Tetrahedron Lett. 55:4709 (1999))and potassium hexamethyl disilazide, to give the alkylation products166.11 and 166.12. The 2′-substituted isomer 166.11 is then reacted, ina Arbuzov reaction, with a trialkyl phosphite to yield the phosphonate166.13. The Arbuzov reaction is described in Handb. OrganophosphorusChem. 115 (1992). In this procedure, in which a bromo substituent isconverted into the corresponding phosphonate, the substrate is heated atfrom about 60° C. to about 160° C. with a five to fifty-fold molarexcess of a trialkyl phosphite, to effect the transformation.

The 2′-substituted pyrazole 166.14 is reacted at 70° C. indimethylformamide solution with one molar equivalent of a dialkyl3-aminophenyl phosphonate 166.14 and cesium carbonate, to give the aminephosphonate 166.15.

Using the above procedures, but employing different dibromides, and/ordifferent amino-substituted phosphonates, products analogous to 166.13and 166.15 are obtained.

EXAMPLES 167-170 Deflazacort Derivatives

The synthesis of representative phosphonate derivatives of deflazacortis outlined in Examples 167-170. In these Examples, it may be necessaryto protect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 167 Preparation of Representative Deflazacort Derivatives

Representative compounds of the invention can be prepared as illustratedabove. Deflazacort 167.1 (U.S. Pat. No. 3,436,389) is protected toafford the derivative 167.2. The ketone is protected, for example, byconversion to the cyclic ethylene ketal, by reaction in toluene solutionat reflux temperature with ethylene glycol and an acid catalyst, asdescribed in J. Am. Chem. Soc., 77:1904 (1955). Deprotection is effectedby reaction with pyridinium tosylate in aqueous acetone, as described inJ. Chem. Soc. Chem. Comm. 1351 (1987).

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 167.1 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn. 50:102 (1970). The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc. 101:5841 (1979).

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 167.1 is reacted with titaniumtetrakis-(diethylamide), as described in J. Chem. Soc. Chem. Comm. 406(1983), to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The protected compound 167.2 is then converted into thephosphonate-containing analog 167.3, using the procedures describedbelow, and the protecting group is then removed, as described above, togive the phosphonate 167.4.

EXAMPLE 168 Preparation of Representative Deflazacort Derivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain asillustrated above. In this procedure, the protected derivative 168.1 isreacted with an amine or hydroxylamine 168.2, in which R² is an alkyl,alkenyl, cycloalkyl or cycloalkenyl group, optionally incorporating aheteroatom O, S or N, or a functional group such as an amide, ester,oxime, sulfoxide or sulfone etc, or an optionally substituted aryl,heteroaryl or aralkyl group, optionally incorporating a heteroatom O, Sor N, and X is either a phosphonate group or a group which issubsequently converted into a phosphonate-containing substituent. Forexample, X is dialkylphosphono, bromo, hydroxy, amino, carboxy and thelike. The reaction is conducted between equimolar amounts of thereactants in an aprotic solvent such as pyridine or xylene, or in analcoholic solvent such as ethanol, optionally in the presence of an acidcatalyst, to give the imine or oxime 168.3. The preparation of oximes ofsteroidal 3-ketones is described in Anal. Bioch. 86:133 (1978) and in J.Mass. Spectrom. 30:497 (1995). The protecting group is then removed toafford the 20-keto phosphonate product 168.4.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated. In this procedure, a phosphonate 168.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine 168.6 (Aldrich) to produce the ether168.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether 168.8. Theabove procedure is also employed for the preparation of substitutedhydroxylamines which are precursors to phosphonates.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group as illustrated above. In this procedure, thesubstrate 168.1, in which the 20-ketone is protected as the dimethylhydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine 168.8a, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett. 27:1477(1986)) and BOC-hydroxylamine, to afford the oxime 168.10. Deprotectionthen affords the 20-keto phosphonate 168.11. The oxime forming reactionis performed at ambient temperature in ethanol-acetic acid solutionbetween equimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 168.8a, different oxime ethers 168.2, the corresponding products168.4 are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a phenylethoxy oxime group as illustrated above. In thisprocedure, the dienone 168.1, in which the 20-ketone is protected as thedimethyl hydrazone, is reacted, as described above, withO-(3-bromo-phenylethoxy)hydroxylamine 168.9, prepared as described abovefrom 3-bromophenylethyl bromide (French Patent FR 1481052), andBOC-protected hydroxylamine 168.6, to give the oxime 168.12. Theprotecting group is then removed to yield the 20-keto product 168.13.The latter product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphite 168.14 to afford the phosphonate168.15. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem. 35:1371 (1992). The reaction is performed at ca. 100° C. inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 168.13 is coupled with a dialkylpropenyl phosphonate 168.16 (Aldrich) to afford the phosphonate 168.17.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res. 12:146(1979). The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 168.17 isreduced, for example by reaction with diimide, to produce the saturatedanalog 168.18. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromophenylethyl reagent 168.9, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, products analogous to the compounds 168.15, 168.17 and168.18 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of a 3-phenylimino group as illustrated above. In this procedure,the substrate 168.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with a dialkyl 3-aminophenyl phosphonate168.20 (J. Med. Chem. 27:654 (1984)), to give, after deprotection, theimine product 168.21. The imine forming reaction is conducted in ahydrocarbon solvent such as toluene or xylene, at reflux temperature, inthe presence of a basic catalyst such as sodium methoxide, or an acidcatalyst such as p-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the 3-aminophenylphosphonate 168.20 different amino-substituted aryl or heteroarylphosphonates, products analogous to 168.21 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and a carbamate linkage as illustrated above.In this procedure, the dienone 168.1, in which the 20-ketone isprotected as the dimethylhydrazone, is reacted withO-(2-hydroxyethyl)hydroxylamine 168.22 (J. Chem. Soc. Chem. Comm. 903(1986)) to yield the oxime 168.23. The reaction of steroidal1,4-dien-3-ones with substituted hydroxylamines is described in J.Steroid Bioch. 7:795 (1976); the reaction is performed between equimolaramounts of the reactants in a polar organic solvent such as pyridine ormethanol, optionally in the presence of acetic acid or sodium acetate.The product 168.23 is then coupled with a dialkyl 4-aminophenylphosphonate 168.24 (Epsilon) and carbonyl diimidazole, to yield, afterdeprotection, the carbamate oxime 168.25. The preparation of carbamatesis described in Comprehensive Organic Functional Group TransformationsVol. 6 416ff (A. R. Katritzky, ed., Pergamon, 1995) and in S. R. Sandlerand W. Karo, Organic Functional Group Preparations 260ff (AcademicPress, 1986). In the procedure, the amine is reacted in an inert aproticsolvent such as dichloromethane or tetrahydrofuran, with phosgene or afunctional equivalent thereof, such as carbonyl diimidazole,triphosgene, pentafluorophenyl carbonate and the like, to afford thecorresponding activated acylamine. The latter compound is then reactedwith an alcohol to yield the carbamate.

Using the above procedures, but employing, in place of thehydroxy-substituted hydroxylamine 168.22, different hydroxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates, theproducts analogous to 168.25 are obtained.

EXAMPLE 169 Preparation of Representative Deflazacort Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and/or a variablecarbon chain as illustrated above. In this procedure, the dienone 167.1is reduced to afford the 1,2-dihydro product 169.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example, as describedin J. Med. Chem. 44:602 (2001). The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc. 86:1520(1964), to afford the 2-formyl product 169.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 169.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles169.4 and 169.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc. 86:1520 (1964). The pyrazoles169.4 and 169.5 are then transformed into the phosphonates 169.6 and169.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of an amide linkage is illustrated above. In this procedure, theketoaldehyde 169.2 is reacted, as described above, with 3-carboxyphenylhydrazine 169.8 (Apin) to give the pyrazoles 169.9 and 169.10. The2′-substituted isomer 169.9 is then coupled in dimethylformamidesolution at ambient temperature with a dialkyl 3-aminopropyl phosphonate169.11 (Acros) and dicyclohexyl carbodiimide, to yield the amidephosphonate 169.12. The preparation of amides from carboxylic acids andderivatives is described, for example, in S. R. Sandler and W. Karo,Organic Functional Group Preparations 274 (Academic Press, 1986), and R.C. Larock, Comprehensive Organic Transformations 972ff (VCH, 1989). Thecarboxylic acid is reacted with the amine in the presence of anactivating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The isomeric pyrazole 169.10 is reacted, as described above, with adialkyl 2-aminophenyl phosphonate 169.13 (Acros) to yield the amidephosphonate 169.14.

Using the above procedures, but employing different carboxy-substitutedhydrazines, and/or different amino-substituted phosphonates, theproducts analogous to 169.12 and 169.14 are obtained.

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl group and a hydrazone or acyl hydrazinelinkage is illustrated above. In this procedure, the ketoaldehyde 169.2is reacted, as described above, with 1,3-bis(hydrazino)benzene 169.15(Bull. Soc. Chim. Fr. 1371 (1975)) to produce the pyrazoles 169.16 and169.17. The 2′-substituted isomer 169.16 is reacted in tetrahydrofuransolution at ambient temperature with one molar equivalent of adialkylphosphono acetaldehyde (Aurora), to give the hydrazonephosphonate 169.19.

Alternatively, the 1′-substituted pyrazole 169.17 is coupled, asdescribed above, with a dialkylphosphono butyric acid 169.20 (Epsilon)and dicyclohexyl carbodiimide to prepare the phosphonate 169.21.

Using the above procedures, but employing, in place of the1,3-bis(hydrazino)phenyl hydrazine 169.15, different bis hydrazines,and/or different dialkyl formyl or carboxy-substituted phosphonates, theproducts analogous to the compounds 169.19 and 169.21 are obtained.

EXAMPLE 170 Preparation of Representative Deflazacort Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage as illustrated above.In this procedure, the ketoaldehyde 169.2 is reacted with hydrazine toafford the pyrazole derivative 170.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc.86:1520 (1964). The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 170.2, in which R² and X are as defined above, or a reactivebromoheteroaromatic reagent, to yield the alkylation products 170.3 and170.4. The alkylation of substituted pyrazoles is described, forexample, in T. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992).The reaction is performed between equimolar amounts of the substrates ina polar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as dimethylaminopyridine, lithiumhexamethyldisilazide and the like. The products 170.3 and 170.4 are,except in cases where X is dialkylphosphono, converted into thephosphonates 170.5 and 170.6, using the procedures described herein.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 170.1 is reacted in dimethylformamide solution at70° C. with one molar equivalent of a dialkyl bromopropyl phosphonate170.7 (Synthelec) and cesium carbonate, to give the pyrazoles 170.8 and170.9.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 170.1 is reacted in tetrahydrofuran solution with1,4-bis(bromomethyl)benzene 170.10 and potassium hexamethyl disilazide,to give the alkylation products 170.11 and 170.12. The 2′-substitutedisomer 170.11 is then reacted, in an Arbuzov reaction, with a trialkylphosphite to yield the phosphonate 170.13. The Arbuzov reaction isdescribed in Handb. Organophosphorus Chem. 115 (1992). In thisprocedure, in which a bromo substituent is converted into thecorresponding phosphonate, the substrate is heated at from about 60° C.to about 160° C. with a five to fifty-fold molar excess of a trialkylphosphite, to effect the transformation.

The 2′-substituted pyrazole 170.14 is reacted at 70° C. indimethylformamide solution with one molar equivalent of a dialkylmercaptoethyl phosphonate 170.14 (Zh. Obschei. Khim. 43:2364 (1973)) andcesium carbonate, to give the thioether phosphonate 170.15.

Using the above procedures, but employing different dibromides, and/ordifferent mercapto-substituted phosphonates, products analogous to170.13 and 170.15 are obtained.

EXAMPLES 171-174 Flunisolide Derivatives

The synthesis of representative phosphonate derivatives of Flunisolideis outlined in Examples 171-174. In these Examples, it may be necessaryto protect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, 1972, p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

EXAMPLE 171 Preparation of Representative Flunisolide Derivatives

Representative compounds of the invention can be prepared as illustratedabove. The 20-ketone group and/or the 21-hydroxyl group of Flunisolide171.1 (U.S. Pat. No. 3,124,571) are protected to afford the derivative171.2. The ketone is protected, for example, by conversion to the cyclicethylene ketal, by reaction in toluene solution at reflux temperaturewith ethylene glycol and an acid catalyst, as described in J. Am. Chem.Soc., 77:1904 (1955). Deprotection is effected by reaction withpyridinium tosylate in aqueous acetone, as described in J. Chem. Soc.Chem. Comm. 1351 (1987).

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 171.1 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn. 50:102 (1970). The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc. 101:5841 (1979).

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 171.1 is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc. Chem. Comm. 406(1983), to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The 21-hydroxyl group is protected, for example, by conversion to theacetate ester, by reaction with one molar equivalent of acetyl chloridein dichloromethane/pyridine. The 21-acetoxy group is removed by reactionwith one molar equivalent of lithium hydroxide in aqueousdimethoxyethane.

Alternatively, the 21-hydroxyl group is protected by conversion to thetert.butyl dimethylsilyl ether, by reaction in dimethylformamidesolution with one molar equivalent of tert.butylchlorodimethylsilane andimidazole, as described in J. Am. Chem. Soc. 94:6190 (1972). The silylether is removed by reaction with tetrabutylammonium fluoride intetrahydrofuran solution, as described in J. Am. Chem. Soc. 94:6190(1972).

The protected compound 171.2 is then converted into thephosphonate-containing analog 171.3 and the protecting group or groupsare then removed, as described above, to give the phosphonate 171.4.

EXAMPLE 172 Preparation of Representative Flunisolide Derivatives

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the ketone-protected derivative172.1 is reacted with an amine or hydroxylamine 172.2, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime 172.3. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch. 86:133 (1978) and in J. Mass. Spectrom. 30:497 (1995). Theprotecting group is then removed to afford the 20-keto phosphonateproduct 172.4.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 172.5,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 172.6(Aldrich) to produce the ether 172.7. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 172.8. The above procedure is also employed for the preparation ofsubstituted hydroxylamines which are precursors to phosphonates.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 172.1, in which the 20-ketone is protected as the dimethylhydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine 172.8a, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett. 27:1477(1986)) and BOC-hydroxylamine, to afford the oxime 172.10. Deprotectionaffords the 20-keto phosphonate 172.11. The oxime forming reaction isperformed at ambient temperature in ethanol-acetic acid solution betweenequimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 172.8a, different oxime ethers 172.2, the corresponding products172.4 are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a phenoxyethoxy oxime group is illustrated above. In thisprocedure, the dienone 172.1, in which the 20-ketone is protected as thedimethyl hydrazone, is reacted, as described above, withO-(4-bromophenoxyethoxy)hydroxylamine 172.9, prepared as described abovefrom 4-bromophenoxyethyl bromide (FR 1481052), and BOC-protectedhydroxylamine 172.6, to give the oxime 172.12. The protecting group isthen removed to yield the 20-keto product 172.13. The latter product isthen reacted, in the presence of a palladium catalyst, with a dialkylphosphite 172.14 to afford the phosphonate 172.15. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem. 35:1371 (1992). Thereaction is performed at ca. 100° C. in an inert solvent such astoluene, in the presence of a base such as triethylamine and a catalyticamount of tetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 172.13 is coupled with a dialkylbutenyl phosphonate 172.16 (Org. Lett. 3:217 (2001)) to afford thephosphonate 172.17. The coupling of aryl halides with olefins by meansof the Heck reaction is described, for example, in F. A. Carey and R. J.Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and in Acc.Chem. Res. 12:146 (1979). The aryl bromide and the olefin are coupled ina polar solvent such as dimethylformamide or dioxane, in the presence ofa palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 172.17 isreduced, for example by reaction with diimide, to produce the saturatedanalog 172.18. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromophenoxyethyl reagent 172.9, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, products analogous to the compounds 172.15, 172.17 and172.18 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of a 4-phenylimino group is illustrated above. In this procedure,the substrate 172.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with a dialkyl 4-aminophenyl phosphonate172.20 (Epsilon), to give, after deprotection, the imine product 172.21.The imine forming reaction is conducted in a hydrocarbon solvent such astoluene or xylene, at reflux temperature, in the presence of a basiccatalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the 4-aminophenylphosphonate 172.20 different amino-substituted aryl or heteroarylphosphonates, products analogous to 172.21 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and a thioether linkage is illustrated above.In this procedure, the dienone 172.1, in which the 20-ketone isprotected as the dimethylhydrazone, is reacted with 2-mercaptoethylhydroxylamine 172.22 (Bioorganicheskaya Khim. 12:1662 (1986)) to yieldthe oxime 172.23. The reaction of steroidal 1,4-dien-3-ones withhydroxylamines is described in J. Steroid Bioch. 7:795 (1976). Thereaction is performed between equimolar amounts of the reactants in apolar organic solvent such as pyridine or methanol, optionally in thepresence of acetic acid or sodium acetate. The product 172.23 is thencoupled, in a Mitsonobu reaction, with a dialkyl 3-hydroxyphenylphosphonate 172.24 (Aurora), to yield, after deprotection, the thioetheroxime 172.25. The preparation of aromatic ethers by means of theMitsonobu reaction is described, for example, in R. C. Larock,Comprehensive Organic Transformations 448 (VCH, 1989), in F. A. Careyand R. J. Sundberg, Advanced Organic Chemistry, Part B 153-4 (Plenum,2001), and in Org. React. 42:335, (1992). The phenol and the hydroxyl ormercapto component are reacted together in an aprotic solvent such as,for example, tetrahydrofuran, in the presence of a dialkylazodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.42:335-656 (1992).

Using the above procedures, but employing, in place of themercapto-substituted hydroxylamine 172.24, differentmercapto-substituted hydroxylamines, and/or different hydroxyarylphosphonates, the products analogous to 172.25 are obtained.

EXAMPLE 173 Preparation of Representative Flunisolide Derivatives

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and/or a variablecarbon chain is illustrated above. In this procedure, the dienone 171.2,in which the 21-hydroxyl group is protected is reduced to afford the1,2-dihydro product 173.1. The catalytic hydrogenation reaction iseffected by the use of tris(triphenylphosphine)rhodium (I) chloride, forexample as described in J. Med. Chem. 44:602 (2001). The product is thenreacted with ethyl formate and a base such as sodium hydride, in aninert solvent such as toluene or dimethylformamide, as described in J.Am. Chem. Soc. 86:1520 (1964), to afford the 2-formyl product 173.2.This compound is then reacted with an alkyl, aralkyl, aryl or heteroarylhydrazine 173.3, in which the substituent X is either a phosphonategroup or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields, afterdeprotection of the 21-hydroxyl group, the isomeric 2′- and 1′-arylpyrazoles 173.4 and 173.5. The pyrazole-forming reaction is performedbetween equimolar amounts of the reactants in an acidic solvent such asacetic acid, as described in J. Am. Chem. Soc. 86:1520 (1964). Thepyrazoles 173.4 and 173.5 are then transformed into the phosphonates173.6 and 173.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of a carbamate or an amine linkage is illustrated above. In thisprocedure, the ketoaldehyde 173.2 is reacted, as described above, with4-aminophenyl hydrazine 173.8 (Syn. Comm. 4:57 (1974)) to give thepyrazoles 173.9 and 173.10. The 2′-substituted isomer 173.9 is thenreacted in dichloromethane solution with one molar equivalent of adialkyl 2-hydroxyethyl phosphonate 173.11 (Aldrich) and carbonyldiimidazole (CDI) to give the carbamate 173.12. The preparation ofcarbamates is described in Comprehensive Organic Functional GroupTransformations Vol. 6 416ff (A. R. Katritzky, ed., Pergamon, 1995) andin S. R. Sandler and W. Karo, Organic Functional Group Preparations260ff (Academic Press, 1986). In the procedure, the amine is reacted inan inert aprotic solvent such as dichloromethane or tetrahydrofuran,with phosgene or a functional equivalent thereof, such as carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate and the like, toafford the corresponding activated acylamine. The latter compound isthen reacted with an alcohol to yield the carbamate.

The isomeric pyrazole 173.10 is reacted in a reductive aminationprocedure, in tetrahydrofuran solution at ambient temperature, with onemolar equivalent of a dialkyl 4-formylphenyl phosphonate 173.13(Epsilon) and sodium cyanoborohydride to yield the amine phosphonate173.14. The preparation of amines by means of reductive aminationprocedures is described, for example, in R. C. Larock, ComprehensiveOrganic Transformations, 421 (VCH) and in F. A. Carey and R. J.Sundberg, Advanced Organic Chemistry Part B 269 (Plenum, 2001). In thisprocedure, the amine component and the aldehyde or ketone component arereacted together in the presence of a reducing agent such as, forexample, borane, sodium cyanoborohydride, sodium triacetoxyborohydrideor diisobutylaluminum hydride, optionally in the presence of a Lewisacid, such as titanium tetraisopropoxide, as described in J. Org. Chem.55:2552 (1990).

Using the above procedures, but employing different amino-substitutedhydrazines, and/or different hydroxy- or formyl-substitutedphosphonates, the products analogous to 173.12 and 173.14 are obtained.

The preparation of the phosphonates in which the phosphonate group isattached by means of a propenyl group and an aromatic ring isillustrated above. In this procedure, the ketoaldehyde 173.2 is reacted,as described above, with allyl hydrazine 173.15 (Zh. Org. Khim. 3:983(1967)) to produce the pyrazoles 173.16 and 173.17. The 2′-substitutedisomer 173.16 is then coupled by means of a Heck reaction, as describedabove, with a dialkyl 5-bromo-2-thienylmethyl phosphonate 173.18 (Syn.455 (2003)) to give the phosphonate 173.19.

Alternatively, the 1′-substituted pyrazole 173.22 is coupled in a Heckreaction, as described above, with a dialkyl 4-bromophenyl phosphonate173.20 (J. Organomet. Chem. 581:62 (1999)) to prepare the phenylpropenylphosphonate 173.21.

Using the above procedures, but employing, in place of the allylhydrazine 173.15, different alkenyl hydrazines, and/or different dialkylbromo-substituted phosphonates, the products analogous to the compounds173.19 and 173.21 are obtained.

EXAMPLE 174 Preparation of Representative Flunisolide Derivatives

The preparation of phosphonate esters in which the phosphonate group isattached by means of a variable carbon linkage is illustrated above. Inthis procedure, the ketoaldehyde 173.2 is reacted with hydrazine toafford the pyrazole derivative 174.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc.86:1520 (1964). The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 174.2, in which R² and X are as defined above, or a reactivebromoheteroaromatic reagent, to yield the alkylation products 174.3 and174.4. The alkylation of substituted pyrazoles is described, forexample, in T. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992).The reaction is performed between equimolar amounts of the substrates ina polar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as dimethylaminopyridine, lithiumhexamethyldisilazide and the like. The products 174.3 and 174.4 are,except in cases where X is dialkylphosphono, converted into thephosphonates 174.5 and 174.6, using the procedures described herein.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 174.1 is reacted in dimethylformamide solution at70° C. with one molar equivalent of 2,5-dibromothiazole 174.7 (Aldrich)and lithium hexamethyl disilazide, to give the pyrazoles 174.8a and174.9a. The products are then coupled, as described above, with adialkyl phosphite to yield the phosphonates 174.8b and 174.9b.

Using the above procedures, but employing different dibromo-substitutedheterocycles, the products analogous to 174.8b and 174.9b are obtained.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 174.1 is reacted in tetrahydrofuran solution withone molar equivalent of 3,5-bis(chloromethyl)pyridine 174.10 (Eur. J.Inorg. Chem. 2:163 (1998)) and potassium hexamethyl disilazide, to givethe alkylation products 174.11 and 174.12. The 2′-substituted isomer174.11 is then reacted, in an Arbuzov reaction, with a trialkylphosphite and a catalytic amount of potassium bromide, to yield thephosphonate 174.13. The Arbuzov reaction is described in Handb.Organophosphorus Chem. 115 (1992). In this procedure, in which a halosubstituent is converted into the corresponding phosphonate, thesubstrate is heated at from about 60° C. to about 160° C. with a five tofifty-fold molar excess of a trialkyl phosphite, to effect thetransformation.

The 2′-substituted pyrazole 174.12 is reacted at 70° C. indimethylformamide solution with one molar equivalent of a dialkylhydroxymethyl phosphonate 174.14 (Aldrich) and cesium carbonate, to givethe ether phosphonate 174.15.

Using the above procedures, but employing different dihalides, and/ordifferent hydroxyl-substituted phosphonates, products analogous to174.13 and 174.15 are obtained.

EXAMPLES 175-178 Medroxyprogesterone Derivatives

The synthesis of representative phosphonate derivatives ofmedroxyprogesterone is outlined in Examples 175-178. In these Examples,it may be necessary to protect certain reactive substituents fromunwanted reactions by protection before the sequence described, and todeprotect the substituents afterwards, according to the knowledge of oneskilled in the art. Protection and deprotection of functional groups aredescribed, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990. The protectionand deprotection of steroidal ketones and alcohols is described inOrganic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J. A.Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactive substituentswhich may be protected are shown in the accompanying schemes as, forexample, [OH], [O], etc.

EXAMPLE 175 Preparation of Representative Medroxyprogesterone

Representative compounds of the invention can be prepared as illustratedabove. The 20-ketone group of medroxyprogesterone 175.1 (U.S. Pat. Nos.3,043,832, 3,061,616, and 3,377,364) is protected to afford thederivative 175.2. The ketone is protected, for example, by conversion tothe cyclic ethylene ketal, by reaction in toluene solution at refluxtemperature with ethylene glycol and an acid catalyst, as described inJ. Am. Chem. Soc., 77:1904 (1955). Deprotection is effected by reactionwith pyridinium tosylate in aqueous acetone, as described in J. Chem.Soc. Chem. Comm. 1351 (1987).

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 175.1 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn. 50:102 (1970). The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc. 101:5841 (1979).

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 175.1 is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc. Chem. Comm. 406(1983), to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The protected compound 175.2 is then converted into thephosphonate-containing analog 175.3, using the procedures describedbelow, and the protecting group or groups are then removed, as describedabove, to give the phosphonate 175.4.

EXAMPLE 176 Preparation of Representative Medroxyprogesterone

The preparation of phosphonates in which the phosphonate is attached bymeans of an imine or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the ketone-protected derivative176.1 is reacted with a hydroxylamine or amine 176.2, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the oxime 176.3. The preparationof oximes of steroidal 3-ketones is described in Anal. Bioch. 86:133(1978) and in J. Mass. Spectrom. 30:497 (1995). The protecting group isthen removed to afford the 20-keto phosphonate product 176.4.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated. In this procedure, a phosphonate 176.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine 176.6 (Aldrich) to produce the ether176.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether 176.8. Theabove procedure is also employed for the preparation of substitutedhydroxylamines which are precursors to phosphonates.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 176.1, in which the 20-ketone is protected as the dimethylhydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine 176.8a, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett. 27:1477(1986)) and BOC-hydroxylamine, to afford the oxime 176.10. Deprotectionaffords the 20-keto phosphonate 176.11. The oxime forming reaction isperformed at ambient temperature in ethanol-acetic acid solution betweenequimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 176.8a, different oxime ethers 176.2, the corresponding products176.4 are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a pyridylmethoxy oxime group is illustrated above. In thisprocedure, the enone 176.1, in which the 20-ketone is protected as thedimethyl hydrazone, is reacted, as described above, withO-(5-bromo-3-pyridylmethoxy)hydroxylamine 176.9, prepared as describedabove from 5-bromo-3-bromomethylpyridine (WO 9528400) and BOC-protectedhydroxylamine 176.6, to give the oxime 176.12. The protecting group isthen removed to yield the 20-keto product 176.13. The latter product isthen reacted, in the presence of a palladium catalyst, with a dialkylphosphite 176.14 to afford the phosphonate 176.15. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem. 35:1371 (1992). Thereaction is performed at ca. 100° C. in an inert solvent such astoluene, in the presence of a base such as triethylamine and a catalyticamount of tetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 176.13 is coupled with a dialkylvinylphosphonate 176.16 (Aldrich) to afford the phosphonate 176.17. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res. 12:146(1979). The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxane, in the presence of a palladium(0)catalyst such as tetrakis(triphenylphosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 176.17 isreduced, for example by reaction with diimide, to produce the saturatedanalog 176.18. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromopyridylreagent 176.9, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, productsanalogous to the compounds 176.15, 176.17 and 176.18 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and a carbamate linkage is illustrated above.In this procedure, the enone 176.1, in which the 20-ketone is protectedas the dimethylhydrazone, is reacted with 2-hydroxyethyl hydroxylamine176.20 (J. Chem. Soc. Chem. Comm. 903 (1986)) to yield the oxime 176.21.The reaction of unsaturated steroidal ketones with hydroxylamines isdescribed in J. Steroid Bioch. 7:795 (1976). The reaction is performedbetween equimolar amounts of the reactants in a polar organic solventsuch as pyridine or methanol, optionally in the presence of acetic acidor sodium acetate. The product 176.21 is then coupled with a dialkyl4-aminophenyl phosphonate 176.22 (Epsilon) and carbonyl diimidazole, toyield, after deprotection, the carbamate oxime 176.23. The preparationof carbamates is described in Comprehensive Organic Functional GroupTransformations Vol. 6 416ff (A. R. Katritzky, ed., Pergamon, 1995) andin S. R. Sandler and W. Karo, Organic Functional Group Preparations260ff (Academic Press, 1986). In the procedure, the amine is reacted inan inert aprotic solvent such as dichloromethane or tetrahydrofuran,with phosgene or a functional equivalent thereof, such as carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate and the like, toafford the corresponding activated acylamine. The latter compound isthen reacted with an alcohol to yield the carbamate.

Using the above procedures, but employing, in place of thehydroxy-substituted hydroxylamine 176.20, different hydroxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates, theproducts analogous to 176.23 are obtained.

EXAMPLE 177 Preparation of Representative Medroxyprogesterone

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and/or a variablecarbon chain is illustrated above. In this procedure, the enone 177.1 inwhich the 20-ketone is protected as the cyclic ethylene ketal, isreacted with ethyl formate and a base such as sodium hydride, in aninert solvent such as toluene or dimethylformamide, as described in J.Am. Chem. Soc. 86:1520 (1964), to afford the 2-formyl product 177.2.This compound is then reacted with an alkyl, aralkyl, aryl or heteroarylhydrazine 177.3, in which the substituent X is either a phosphonategroup or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields, afterdeprotection of the 20-ketone, the isomeric 2′- and 1′-aryl pyrazoles177.4 and 177.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc. 86:1520 (1964). The pyrazoles177.4 and 177.5 are then transformed into the phosphonates 177.6 and177.7.

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl ring and an amide linkage is illustrated above. Inthis procedure, the ketoaldehyde 177.2 is reacted, as described above,with 3-carboxyphenyl hydrazine 177.8 (Apin) to give the pyrazoles 177.9and 177.10. The 2′-substituted isomer 177.9 is then reacted indimethylformamide solution at ambient temperature with one molarequivalent of a dialkyl 2-aminoethyl phosphonate 177.11 (Aldrich) anddicyclohexyl carbodiimide, to give the amide phosphonate 177.12. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in S. R. Sandler and W. Karo, Organic FunctionalGroup Preparations 274 (Academic Press, 1968) and R. C. Larock,Comprehensive Organic Transformations 972ff (VCH, 1989). The carboxylicacid is reacted with the amine in the presence of an activating agent,such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The isomeric pyrazole 177.10 is reacted, as described above, with onemolar equivalent of a dialkyl 4-amino-2-thienyl phosphonate R2.20,prepared by the palladium catalyzed coupling reaction, as describedabove, between 4-amino-2-bromothiophene (Tetrahedron Lett. 43:3295(1987)) and a dialkyl phosphite, to give the amide phosphonate 177.14.

Using the above procedures, but employing different carboxy-substitutedhydrazines, and/or different amino-substituted phosphonates, theproducts analogous to 177.12 and 177.14 are obtained.

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl group or a phenyl group and a carbon chainis illustrated above. In this procedure, the ketoaldehyde 177.2 isreacted, as described above, with 3-bromophenyl hydrazine 177.15 (Fluka)to produce the pyrazoles 177.16 and 177.17. The 2′-substituted isomer177.16 is then coupled, as described above, with a dialkyl phosphite177.18 to afford the phosphonate 177.19.

Alternatively, the 1′-substituted pyrazole 177.17 is coupled, asdescribed above, with a dialkyl vinylphosphonate 177.20 (Aldrich) and apalladium catalyst to prepare the vinyl phosphonate 177.21a. Optionally,the product is reduced, as described above, to give the analog 177.21b.

Using the above procedures, but employing, in place of the bromophenylhydrazine 177.15, different bromo-substituted hydrazines, and/ordifferent dialkyl alkenyl phosphonates, the products analogous to thecompounds 177.19 and 177.21 are obtained.

EXAMPLE 178 Preparation of Representative Medroxyprogesterone

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde 177.2 is reacted with hydrazine toafford, after deprotection of the 20-ketone, the pyrazole derivative178.1. The reaction of steroidal 2-formyl-3-ketones with hydrazine isdescribed in J. Am. Chem. Soc. 86:1520 (1964). The reaction is performedin acetic acid at ambient temperature. The pyrazole product is thenreacted with a bromomethyl compound 178.2, in which R² and X are asdefined above, or a reactive Tbromoheteroaromatic reagent, to yield thealkylation products 178.3 and 178.4. The alkylation of substitutedpyrazoles is described, for example, in T. L. Gilchrist, HeterocyclicChemistry 309 (Longman, 1992). The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 178.3 and 178.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 178.5 and 178.6, usingthe procedures described herein.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 178.1 is reacted in dimethylformamide solution at70° C. with one molar equivalent of a dialkyl 4-bromomethyl phosphonate178.7 (Lancaster) and lithium hexamethyl disilazide, to give thepyrazoles 178.8 and 178.9.

Using the above procedures, but employing different bromo-substitutedphosphonates, the products analogous to 178.8 and 178.9 are obtained.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 178.1 is reacted in tetrahydrofuran solution with4-bromomethyl cyclohexanone 178.10 (WO 9737959) and potassium hexamethyldisilazide, to give the alkylation products 178.11 and 178.12. The2′-substituted isomer 178.11 is then reacted, in a reductive aminationreaction, with a dialkyl aminomethyl phosphonate 178.14 (Interchim) andsodium triacetoxy borohydride, to yield the amine phosphonate 178.13.The preparation of amines by means of reductive amination procedures isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations 421 (VCH) and in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B 269 (Plenum, 2001). In thisprocedure, the amine component and the aldehyde or ketone component arereacted together in the presence of a reducing agent such as, forexample, borane, sodium cyanoborohydride, sodium triacetoxyborohydrideor diisobutylaluminum hydride, optionally in the presence of a Lewisacid, such as titanium tetraisopropoxide, as described in J. Org. Chem.55:2552 (1990).

The 1′-substituted pyrazole 178.12 is converted by the same reactioninto the isomeric amine phosphonate 178.15.

Using the above procedures, but employing different bromo-substitutedaldehydes and ketones, and/or different amino-substituted phosphonates,products analogous to 178.13 and 178.15 are obtained.

EXAMPLE 179 Preparation of Representative Compounds of Formula 180

As illustrated above, derivatives of the C-21 primary hydroxy group arereadily prepared by alkylating triamcinolone acetonide with theappropriate phosphonate. A specific compound of the invention can beprepared as follows.

After chemoselective extraction of the primary hydroxy proton in 179.1using one equivalent of sodium hydride, the phosphonate triflate isadded to provide the ether 179.5.

EXAMPLE 180 Preparation of Representative Compounds of Formula 181

As illustrated above, by taking advantage of the reactivity differencebetween the primary and secondary hydroxy groups, the primary hydroxygroup is masked by an appropriate protecting group. After alkylation atthe secondary hydroxy moiety of 180.6 with a leaving group-attachedphosphonate and subsequent deprotection, desired analog 180.3 isobtained. A specific compound of the invention can be prepared asfollows.

Triamcinolone acetonide 180.1 is chemoselectively protected as its silylether using the standard TBSCl and imidazole conditions. (J. Am. Chem.Soc. 1972, 94, 6190) Alkylation at the exposed secondary hydroxy groupwith sodium hydride and the phosphonate triflate furnishes theintermediate 180.9. Final TBAF deprotection of the silyl ether affordsthe desired product 180.10.

EXAMPLE 181 Preparation of Representative Compounds of Formula 182

Representative compounds of the invention can be prepared as illustratedabove. Phosphonate derivatives of the acetal are readily prepared fromacidic hydrolysis of triamcinolone acetonide 181.1 to the diol 181.11.Acetylization of the diol with a phosphonate aldehyde furnishes thedesired acetal 181.4. A specific compound of the invention can beprepared as illustrated below.

Triamcinolone acetonide 181.1 is first hydrolized in aqueous aceticacid. (Can. J. Chem. 1983, 61, 634). The resulting diol 181.11 isacetalized with the phosphonate aldehyde and perchloric acid, affordingthe acetal 181.12. (J. Med. Chem. 1996, 39, 4888-4896)

EXAMPLE 182 Preparation of Representative Compounds of Formula 183

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-11 hydroxy group is accomplished throughalkylation of rimexolone 182.1 with the appropriate phosphonate,furnishing analogs of formula 182.2. A specific compound of theinvention can be prepared as illustrated below.

After sodium hydride extraction of the hydroxy proton in 182.1, diethylphosphonate triflate is added to afford ether 182.5.

EXAMPLE 183 Preparation of Representative Compounds of Formula 184

Representative compounds of the invention can be prepared as illustratedabove. Derivatives of the carbonyl at C-17 are readily prepared fromsaponification of fluticasone to the carboxylic acid 183.5. Activationof the carboxylic acid, followed by reaction with thiophosphonate oraminophosphonate nucleophile furnishes the desired thioester 183.1 andamide 183.2, respectively. Specific compounds of the invention can beprepared as follows.

Fluticasone is first saponified with potassium hydroxide in acetone.(Synthesis 2002, 921-927) The resulting carboxylic acid 183.5 isactivated to the carboxylic acid imidazole by the addition of1,1′-carbonyldiimidazole (CDI). (J. Med. Chem. 1994, 37, 3717-3729)Treatment with the thiophosphonate affords thioester 183.6. Magnesiumethoxide may be added to help enhance the reactivity. (Tetrahedron Lett.1981, 22, 3245-3246) Alternatively, the carboimidazole intermediatederived from 183.5 can be reacted with the aminophosphonate to produceamide 183.7.

EXAMPLE 184 Preparation of Representative Compounds of Formula 186

Representative compounds of the invention can be prepared as illustratedabove. The less sterically hindered C-11 hydroxy group of compound 184.1is selectively alkylated with the appropriate phosponate to give analogsof formula 184.3. A specific compound of the invention can be preparedas follows.

After regioselective extraction of the C-11 hydroxy proton in 184.1using one equivalent of sodium hydride, the phosphonate triflate isadded to provide the ether 184.8.

EXAMPLE 185 Preparation of Representative Compounds of Formula 187

Representative compounds of the invention can be prepared as illustratedabove. Again taking advantage of the reactivity difference between C-11and C-17 hydroxy groups, the C-11 hydroxy group is masked by anappropriate protecting group. After alkylation at the C-17 hydroxymoiety of 185.9 with a leaving group-attached phosphonate and subsequentdeprotection, desired analog 185.4 is obtained. A specific compound ofthe invention can be prepared as follows.

Fluticasone 185.1 is regioselectively protected as its C-11 acetateester using the standard acetic anhydride and DMAP conditions. (J. Org.Chem. 1998, 63, 2342-2347) Alkcylation at the exposed C-17 hydroxy groupwith sodium hydride and the phosphonate triflate furnishes theintermediate 185.12. Final ammonia deprotection of the acetate affordsthe desired ether 185.13.

EXAMPLE 186 Preparation of Representative Compounds of Formula 189

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-11 hydroxy group is accomplished throughalkylation of mometasone fuorate 186.1 with the appropriate phosphonate,furnishing analogs of formula 186.2. A specific compound of theinvention can be prepared as follows.

After sodium hydride extraction of the hydroxy proton in 186.1, diethylphosphonate triflate is added to afford ether 186.4.

EXAMPLE 187 Preparation of Representative Compounds of Formula 188

Representative compounds of the invention can be prepared as illustratedabove. Following protection of the only exposed hydroxy group inmometasone fuorate 187.1, intermediate 187.5 is saponified to givealcohol 187.7. Alkylation at the C-17 hydroxy group with the appropriatephosphonate and subsequent deprotection provides the desired product187.3. A specific compound of the invention can be prepared as follows.

Mometasone fuorate 187.1 is protected as its silyl ether using thestandard TBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94,6190). Saponification of the fuoryl ester moiety using aqueous sodiumhydroxide provides the alcohol 187.9. (J. Chem. Soc. Perkin Trans. 11993, 12,1359-1366) The tertiary hydroxy group is alkylated by theaddition of sodium hydroxide and the phosphonate triflate. Afterdeprotection of the silyl ether in intermediate 187.10 with TBAF,diethyl phosponate 187.11 results.

EXAMPLE 188 Preparation of Representative Compounds of Formula 192

Representative compounds of the invention can be prepared as illustratedabove. Since the sodium sulfonate moiety in methylprednisolonesuleptanate 188.1 is the most nucleophilic site in the molecule,syntheses of analogs typically involve protection of or late stageinstallation of the sulfonate functional group. To employ the latterstrategy, 188.1 is first saponified to furnish the triol 188.5.Alkylation at the primary hydroxy group with the appropriate phosphonatefurnishes analogs of formula 188.2. A specific compound of the inventioncan be prepared as follows.

Hydrolysis of the suleptanate ester in 188.1 is accomplished by usingaqueous sodium hydroxide, producing the triol 188.5. The less stericallyhindered primary hydroxy group is alkylated by the addition of sodiumhydroxide and the phosphonate triflate, giving diethyl phosphonate188.6.

EXAMPLE 189 Preparation of Representative Compounds of Formula 190

Representative compounds of the invention can be prepared as illustratedabove. Following protection of the primary hydroxy group, protectedintermediate 189.7 is alkylated at the more exposed C-11 hydroxy site.Deprotection and subsequent installation of the suleptanate esterprovides the desired product 189.3. A specific compound of the inventioncan be prepared as follows.

Triol 189.5 is protected as its silyl ether using the standard TBSCl andimidazole conditions. (J. Am. Chem. Soc. 1972, 94, 6190) Afteralkylating with the diethyl phosphonate triflate, the resultingintermediate 189.11 is treated with TBAF to give the diol 189.12.Attachment of the suleptanate ester is accomplished in four steps:activation of the primary alcohol as its mesylate, Finkelsteinconversion to the iodide (Tetrahedron Lett. 1981, 22, 2055),nucleophilic substitution with octanedioic acid, and final activationand displacement with the secondary amine provides compound 189.13. (J.Pharm. Sci. 1985, 74, 365-374).

EXAMPLE 190 Preparation of Representative Compounds of Formula 191

Representative compounds of the invention can be prepared as illustratedabove. Protection of triol 190.5 at the two less hindered sitesfurnishes alcohol 190.14, which is alkylated at the only exposed hydroxygroup with the appropriate phosphonate. Deprotection and formation ofthe suleptanate ester completes the synthesis of analog 190.4. Aspecific compound of the invention can be prepared as follows.

Triol 190.5 is protected as its TBS ether; however, harsher conditionsshould allow for bis-protection. After alkylating with the diethylphosphonate triflate, the resulting intermediate 190.18 is treated withTBAF to give the diol 190.19. Attachment of the suleptanate ester isaccomplished in four steps: activation of the primary alcohol as itsmesylate, Finkelstein conversion to the iodide (Tetrahedron Lett. 1981,22, 2055), nucleophilic substitution with octanedioic acid, and finalactivation and displacement with the secondary amine provides compound190.20. (J. Pharm. Sci. 1985, 74, 365-374)

EXAMPLE 191 Preparation of Representative Compounds of Formula 193

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-11 hydroxy group is accomplished throughalkylation of beclamethasone 191.1 with the appropriate phosphonate,furnishing analogs of formula 191.2. A specific compound of theinvention can be prepared as follows.

After sodium hydride extraction of the hydroxy proton in compound 191.1,diethyl phosphonate triflate is added to afford ether 191.5.

EXAMPLE 192 Preparation of Representative Compounds of Formula 194

Representative compounds of the invention can be prepared as illustratedabove by exploiting the reactivity differences among the three hydroxygroups available when beclamethasone 192.1 is fully hydrolized.Following protection of the only exposed hydroxy group in 192.1,intermediate 192.6 is saponified to give diol 192.7. Alkylation at theprimary hydroxy group with the appropriate phosphonate and subsequentacylation provides the propionate ester 192.9. The desired product 192.3is achieved after deprotection. A specific compound of the invention canbe prepared as follows.

Beclamethasone 192.1 is protected as its silyl ether using the standardTBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94, 6190).Saponification of both propionic ester moieties using aqueous sodiumhydroxide provides the diol 192.11. The less sterically hindered primaryhydroxy group is alkylated by the addition of sodium hydroxide and thephosphonate triflate. After treating intermediate 192.12 with propionicanhydride in pyridine, the previously hydrolized C-17 propionic ester isreplaced. (J. Med. Chem. 1980, 23, 430-437) TBAF deprotection of thesilyl ether furnishes diethyl phosponate 192.14.

EXAMPLE 193 Preparation of Representative Compounds of Formula 195

Representative compounds of the invention can be prepared as illustratedabove. The two hydroxy groups of diol 193.7 are regioselectivelydifferentiated by protection at the primary site, thus allowingalkylation at the tertiary hydroxy group. The resulting phosphonateintermediate 193.16 is then deprotected to afford the diol 193.17. Themore accessible primary hydroxy group is acylated to produce the desiredanalog 193.4. A specific compound of the invention can be prepared asfollows.

Diol 192.11 (see Example 192) is protected at the primary site as itssilyl ether 193.18. Following alkylation with the diethyl phosphonatetriflate, the resulting intermediate 193.19 is treated with TBAF to givediol 193.20. Propionic anhydride and pyridine are used to generate thefinal product 193.21. (J. Med. Chem. 1980, 23, 430-437)

EXAMPLE 194 Preparation of Representative Compounds of Formula 196

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-11 hydroxy group is accomplished throughalkylation of methylprednisolone aceponate 194.1 with the appropriatephosphonate, furnishing analogs of formula 194.2. A specific compound ofthe invention can be prepared as follows.

After sodium hydride extraction of the hydroxy proton in 194.1, diethylphosphonate triflate is added to afford ether 194.5.

EXAMPLE 195 Preparation of Representative Compounds of Formula 198

Representative compounds of the invention can be prepared as illustratedabove by exploiting the reactivity differences among the three hydroxygroups available when methylprednisolone aceponate 195.1 is fullyhydrolized. Following protection of the only exposed hydroxy group in195.1, intermediate 195.6 is saponified to give diol 195.7. Alkylationat the primary hydroxy group with the appropriate phosphonate andsubsequent acylation provides the propionate ester 195.9. The desiredproduct 195.3 is achieved after deprotection. A specific compound of theinvention can be prepared as follows.

Methylprednisolone aceponate 195.1 is protected as its silyl ether usingthe standard TBSCl and imidazole conditions. (J. Am. Chem. Soc. 1972,94, 6190). Saponification of both ester moieties using aqueous sodiumhydroxide provides the diol 195.11. The less sterically hindered primaryhydroxy group is alkylated by the addition of sodium hydroxide and thephosphonate triflate. After treating intermediate 195.12 with propionicanhydride in pyridine, the previously hydrolized C-17 propionic ester isreplaced. (J. Med. Chem. 1980, 23, 430-437) TBAF deprotection of thesilyl ether furnishes diethyl phosponate 195.14.

EXAMPLE 196 Preparation of Representative Compounds of Formula 197

Representative compounds of the invention can be prepared as illustratedabove. The two hydroxy groups of diol 196.7 are regioselectivelydifferentiated by protection at the primary site, thus allowingalkylation at the tertiary hydroxy group. The resulting phosphonateintermediate 196.16 is then deprotected to afford the diol 196.17. Againthe more accessible primary hydroxy group is acylated to produce thedesired analog 196.4. A specific compound of the invention can beprepared as follows.

Diol 195.11 (see example 195) is protected at the primary site as itssilyl ether 196.18. Following alkylation with the diethyl phosphonatetriflate, the resulting intermediate 196.19 is treated with TBAF to givediol 196.20. Acetic anhydride and pyridine are used to generate thefinal product 196.21. (J. Mol. Biol. 1972, 72, 219).

EXAMPLE 197 Preparation of Representative Compounds of Formula 199

Representative compounds of the invention can be prepared as illustratedabove. The phosphorus containing merimepodib analog 197.2 is synthesizedfrom parent compounds by alkylation. Merimepodib 197.1 is obtained bythe procedure as described in U.S. Pat. No. 6,054,472 and U.S. Pat. No.6,344,465. The methoxy group of merimepodib 197.1 is demethylated tophenolic OH using a suitable reagent, such as boron tribromide. Thephosphonate moiety is introduced to the phenolic OH in a suitableaprotic solvent such as, DMF and is then treated with the phosphonatereagent bearing a leaving group, for example, bromine, mesyl, tosyl, ortrifluoromethanesulfonyl, in the presence of a suitable organic orinorganic base. A specific compound of the invention can be prepared asfollows.

A solution of 197.1 in dichloromethane is treated with boron tribromideto obtain the demethylated compound 197.8. Compound 197.8 is thentreated with cesium carbonate and one equivalent of(trifluoromethanesulfonyloxy)-methylphosphonic acid diethyl ester 197.9to give merimepodib-phosphonate 197.10. Using the above procedure butemploying different phosphonate reagents, the corresponding products197.2 bearing different linking group can be obtained.

EXAMPLE 198 Preparation of Representative Compounds of Formula 201

Representative compounds of the invention can be prepared as illustratedabove. The imidazole containing intermediate 198.13 is synthesized froman aldehyde 198.12 by the procedure of Shih in Tetrahedron Lett. 1993,34, 595. Compound 198.12 is prepared by a two-step procedure describedin U.S. Pat. No. 5,807,876, U.S. Pat. No. 6,054,472, and U.S. Pat. No.6,344,465. The imidazole is protected using suitable reagent, forexample 2-(trimethylsilyl)ethyoxymethyl (SEM) chloride, and the compound198.14 is converted to 198.15 by the similar procedure described for thesynthesis of 197.1 in U.S. Pat. No. 6,054,472 and U.S. Pat. No.6,344,465. After the protecting group on the imidazole of 198.15 isremoved, the phosphonate containing moiety is introduced to theimidazole to provide compounds of the invention. A specific compound ofthe invention can be prepared as follows.

Compound 198.15 is treated with tetrabutylammonium fluoride in THF inreflux condition and the resulting 198.16 is alkylated with 198.9 usingsodium hydride as a base to obtain two isomers 198.17 and 198.18, whichare separated by chromatography.

EXAMPLE 199 Preparation of Representative Compounds of Formula 202

Representative compounds of the invention can be prepared as illustratedabove. Tetrasubstituted benzene derivatives are obtained by literatureprocedures (Ichikawa and Ichibagase Yakugaku Zasshi 1963, 83, 103;Norio, A. et al. Tetrahedron Lett. 1992, 33(37), 5403). After thephenolic OH is protected with a suitable protecting group, for examplebenzyl group, the compound 199.21 is synthesized by the same proceduredescribed in U.S. Pat. No. 6,054,472, and U.S. Pat. No. 6,344,465. Afterthe protecting group is removed, the phosphonate containing moiety isintroduced to the phenolic OH using the phosphonate reagent 199.7,bearing a suitable leaving group. A specific compound of the inventioncan be prepared as follows.

For example, a solution of 199.22, which is obtained by the procedure ofNorio et al. (Tetrahedron Lett. 1992, 33(37), 5403), is treated withsodium hydride and one equivalent of benzyl bromide in DMF to get199.23. Compound 199.23 is converted to 199.24 by a series of steps suchas those reported in U.S. Pat. No. 6,054,472, and U.S. Pat. No.6,344,465. After the benzyl protecting group of 199.24 is removed bycatalytic hydrogenation, a phosphonate bearing moiety is attached byalkylation of the resulting phenol in DMF using sodium hydride and oneequivalent of (trifluoromethanesulfonyloxy)methylphosphonic acid diethylester 199.9 to give 199.25.

EXAMPLE 200 Preparation of Representative Compounds of Formula 203

Representative compounds of the invention can be prepared as illustratedabove. Compound 200.26 is treated with carbonyldiimidazole ortriphosgene followed by the compound 200.27, which has a handle toattach phosphonate moiety. Compound 200.27 bearing an extra substituentis synthesized from the tri substituted phenol with a cyano and a nitrogroups, which is either commercially available or by literatureprocedures (Zolfigol, M. A. et. al. Indian J. Chem. Sect. B 2001,40,1191; De Jongh, R. O. et al. Rec. Trav. Chim. Pays-Bas 1968, 87,1327). The resulting 200.28 is converted to 200.29 using proceduressimilar to those described in U.S. Pat. No. 6,054,472, and U.S. Pat. No.6,344,465. The phosphonate moiety of 200.6 is attached afterdeprotection of the benzyl group of 200.29.

For example, the bromine substituent of compound 200.30 is substitutedwith cyano group by the procedure of De Jongh, R. O. et al. (Recl. Trav.Chim. Pays-Bas 1968, 87, 1327) and the methoxy group is converted tobenzyloxy group as a protecting group, which affords compound 200.31.After selective reduction of cyano to aminomethyl group by borane, theamino group is protected with Boc group and then the reduction of thenitro group using tin (II) chloride generates compound 200.32. Thissubstituted aniline 200.32 is then treated with a reaction mixture ofthe compound 200.26 and carbonyldiimidazole, as described in U.S. Pat.No. 6,054,472, and U.S. Pat. No. 6,344,465, to form the urea 200.33.Compound 200.33 is converted to 200.34. Deprotection of the benzyl groupusing catalytic hydrogenation followed by attachment of a phosphonatemoiety using 200.9 in the presence of cesium carbonate produces compound200.35.

EXAMPLES 201-204

Representative compounds of the invention having the following formulaecan be prepared as described in Examples 201-204.

For example, three regions of mycophenolate mofetil can be utilized forthe attachment of the phosphonate prodrug as demonstrated by compoundsD, E, and G shown above. Also, the carboxylic acid can be replaced witha phosphonic acid as in compound F.

EXAMPLE 201 Preparation of Representative Compounds of Formula 204

Representative compounds of the invention can be prepared as illustratedabove. The morpholino ethyl moiety can serve as a prodrug functionalityto improve bioavailability and can be replaced with the phosphonateprodrug handle as shown above. Mycophenolic acid is commerciallyavailable, e.g., from Sigma Chemical Company, St. Louis, Mo. Activationof the carboxylic acid 201.1 in the presence of the free phenol,followed by addition of an alcohol carrying the phosphonate group,results in the formation of the desired product 201.3 (U.S. Pat. No.4,786,637). A specific compound of the invention can be prepared asfollows.

Mycophenolic acid 201.1 is dissolved in dichloromethane. Thionylchloride is added followed by a catalytic amount of DMF. The reactionmixture is stirred at room temperature for 3 hours, after which thevolatile components are removed under vacuum. The phosphonate-alcohol isdissolved in dichloromethane and chilled to about 4° C. on an ice bath.The mycophenolic acid chloride 201.2 is dissolved in dichloromethane andadded to the chilled solution. After stirring for 90 minutes at about 4°C., the reaction mixture is washed with water and then with aqueoussodium bicarbonate. The organic solution is dried and evaporated toyield the phosphonate 201.3.

EXAMPLE 202 Preparation of Representative Compounds of Formula 207

Representative compounds of the invention can be prepared as illustratedabove. The C-4 phenol position provides a reactive handle for furtheranalogs as illustrated above. Once the carboxylic acid of 202.1 isblocked by morpholino ethyl, such as in compound 202.2 the phenol can bealkylated under basic conditions. Bases such as pyridine, potassiumcarbonate, or triethylamine are utilized. Leaving groups such astrifluoromethylsulfonate, mesylate, bromide, or iodide are attached tothe phosphonate prodrug subunit and reacted, in the presence of base,with compound 202.2. Compound 202.3 can either be used directly, or inthe form of a salt, compound 202.4. Among the large number of salts thatcan be prepared, chloride and bisulfate salts are one particularembodiment of the invention. A specific compound of the invention can beprepared as follows.

Compound 202.5 is prepared similar to compound 201.2 (described inExample 201). A solution of morpholino ethanol in dichloromethane iscooled to about 4° C. The mycophenolic acid chloride 202.5 is dissolvedin dichloromethane and added to the cooled solution. Stirring thissolution for about 90 minutes gives compound 202.2. The reaction mixtureis washed with water and dried with sodium sulfate. Removal of thesolvent provides isolated compound 202.2. Alkylation at the phenolicposition of 202.2 is achieved by suspending the compound in pyridine.Triflate 202.6 is added to the solution and the mixture is stirred atroom temperature for about 90 minutes. The reaction mixture is pouredinto water and the product is extracted with ethyl acetate. Removal ofthe organic layer provides compound 202.7. Hydrochloride salt of 202.7can optionally be prepared. Compound 202.7 is dissolved in isopropanoland the solution is added to a mixture of hydrogen chloride inisopropanol. The hydrochloride salt 202.8 is collected by filtration anddried under vacuum.

EXAMPLE 203 Preparation of Representative Compounds of Formula 205

Representative compounds of the invention can be prepared as illustratedabove. The carboxylic acid of mycophenolic acid can be replaced with aphosphonic acid that may also serves as a prodrug handle. In order toremove the carboxylic acid containing side chain, the acid chloride202.5 (prepared in Example 202) is converted to ester 203.1. Protectionof the phenol with a silyl group, followed by dihydroxylation andcleavage of the diol generates aldehyde 203.3 (Pankiewicz, et al., J.Med. Chem., 2002, 45, 703), (Patterson et al., U.S. Pat. No. 5,444,072)(Example 20). A Wittig reaction with ylide 203.4 carrying anappropriately protected phosphonate provides the desired compound 203.5.Final deprotection yields compound 203.6. A specific compound of theinvention can be prepared as follows.

Mycophenolate ester 203.8 can simply be prepared by stirring the acidchloride 203.7 with MeOH. Then, the phenol position of mycophenolateester is protected by a silyl group such as TBS to provide compound203.9. Once the phenol position is protected, dihydroxylation usingosmium tetraoxide followed by periodinate cleavage provides aldehyde203.10. Aldehyde 203.10 and excess of the ylide 203.11 are heated inbenzene at reflux for about 24 hours. The reaction mixture isconcentrated and the residue is purified by column chromatography toprovide olefin 203.12 (Pankiewics et al., J. Med. Chem., 2002, 45, 703).A final deprotection using HF-pyridine yields the final product 203.13.

EXAMPLE 204 Preparation of Representative Compounds of Formula 208

Representative compounds of the invention can be prepared as illustratedabove. Another attachement point of the compound can be unmasked afterdemethylation of mycophenolate ester 204.2 as illustrated above. Forthis purpose, the 4-OH needs to be masked with a protecting group (P)such as a silyl group. Once the 6-MeO is demethylated and alkylated, theprotecting group at position 4 is removed to reveal the final product204.4. The morphonyl ethanol group is installed early and carriedthrough the alkylation steps. A different protecting group may beinstalled initially and removed later. In such the latter type ofsynthesis, the last step is the formation of the morpholinoethyl esterprodrug. A specific compound of the invention can be prepared asdescribed below.

Phenol 204.5 is protected with TBS group in CH₂Cl₂ using imidazole asbase to yield 204.6. Demethylation is performed using thiolatenucleophiles to generate compound 204.7. A variety of other methods arealso available in literature as described in Protective Groups inOrganic Synthesis by Greene and Wuts. Alklation of the 6-OH using atriflate of the phosphonate proceeds well using K₂CO₃ or TEA to provide204.8. Final deprotection to remove the TBS group provides product204.9.

EXAMPLE 205 Preparation of Representative Compounds of Formula 212

Representative compounds of the invention can be prepared as illustratedabove. Derivatives of the C-21 primary hydroxy group are readilyprepared by alkylating budesonide 205.1 with the appropriatephosphonate. A specific compound of the invention can be prepared asfollows.

After chemoselective extraction of the primary hydroxy proton in 205.1using one equivalent of sodium hydride, the phosphonate triflate isadded to provide the ether 205.5.

EXAMPLE 206 Preparation of Representative Compounds of Formula 211

Representative compounds of the invention can be prepared as illustratedabove. Again taking advantage of the reactivity difference between theprimary and secondary hydroxy groups, the primary hydroxy group ismasked by an appropriate protecting group. After alkylation at thesecondary hydroxy moiety of 206.6 with a leaving group-attachedphosphonate and subsequent deprotection, desired analog 206.3 isobtained. A specific compound of the invention can be prepared asfollows.

Budesonide 206.1 is chemoselectively protected as its silyl ether usingthe standard TBSCl and imidazole conditions. (J. Am. Chem. Soc. 1972,94, 6190) Alkylation at the exposed secondary hydroxy group with sodiumhydride and the phosphonate triflate furnishes the intermediate 206.9.Final TBAF deprotection of the silyl ether affords the desired product206.10.

EXAMPLE 207 Preparation of Representative Compounds of Formula 213

Representative compounds of the invention can be prepared as illustratedabove. Phosphonate derivatives of the acetal are readily prepared fromacidic hydrolysis of budesonide 207.1 to the diol 207.11. Acetylizationof the diol with a phosphonate aldehyde furnishes the desired acetal207.4. A specific compound of the invention can be prepared as follows.

Budesonide 207.1 is first hydrolized in aqueous acetic acid. (J. Am.Chem. Soc. 1987, 109, 1565) The resulting diol 207.11 is acetalized withthe phosphonate aldehyde and perchloric acid, affording the acetal207.12. (J. Med. Chem. 1996, 39, 4888-4896)

EXAMPLE 208 Preparation of Representative Compounds of Formula 220

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-21 hydroxy group is accomplished throughalkylation of dexamethasone 208.1 with the appropriate phosphonate,furnishing analogs of formula 208.2. A specific compound of theinvention can be prepared as follows.

After sodium hydride extraction of the primary hydroxy proton in 208.1,diethyl phosphonate triflate is added to afford ether 208.5.

EXAMPLE 209 Preparation of Representative Compounds of Formulae 215 and218

Representative compounds of the invention can be prepared as illustratedabove. Phosphonate appendages linked to the C-11 hydroxy group can beattained by utilizing protecting groups on dexamethasone 209.1.Following protection of the primary hydroxy group, protectedintermediate 209.6 is alkylated at the more exposed C-11 hydroxy site.Final deprotection provides the desired product 209.3. A specificcompound of the invention can be prepared as follows.

Dexamethasone 209.1 is protected as its silyl ether using the standardTBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94, 6190). Afteralkylating with the diethyl phosphonate triflate, the resultingintermediate 209.9 is treated with TBAF to give the diol 209.10.

EXAMPLE 210 Preparation of Representative Compounds of Formulae 216 and219

Representative compounds of the invention can be prepared as illustratedabove. Protection of dexamethasone 210.1 at the two less hindered sitesfurnishes alcohol 210.11, which is alkylated at the only exposed hydroxygroup with the appropriate phosphonate. Removal of the protecting groupscompletes the construction of analog 210.4. A specific compound of theinvention can be prepared as follows.

Again dexamethasone 210.1 is protected as its TBS ether; however,harsher conditions should allow for bis-protection. After alkylatingwith the diethyl phosphonate triflate, the resulting intermediate 210.14is treated with TBAF to give the desired phosphonate 210.15.

EXAMPLE 211 Preparation of Representative Compounds of Formulae 221-224

Representative compounds of the invention can be prepared as illustratedabove. Specific compounds of the invention can be prepared asillustrated below.

EXAMPLE 212 Preparation of Representative Compounds of Formula 225

Representative macrolide compounds of the invention, wherein thestructure 212.1 is understood to be the compound tacrolimus, ascomycinor sirolimus, can be prepared as illustrated above, for example, usingan aryl bismuth reagent such as that shown is described in Bioorg. Med.Chem. Lett, 1995, 5, 1035. Additionally, silver salts have been used tomediate alkylations on immunosuppresive macrolides such as these: see J.Med. Chem., 1998, 41, 1764. Specific compounds of the invention can beprepared as illustrated below.

EXAMPLE 213 Preparation of a Representative Compound of Formula231-(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (67.0 mg, 177 μmol) in DMF (3.0 mL) wasadded diethyl cyanophosphonate (34.8 μL, 230 μmol) anddiisopropylethylamine (Hunig's Base, DIEA, 30.4 μL, 177 μmol). Thesolution was stirred at ambient temperature for 4 hours whendiethyl(aminomethyl)-phosphonate (45.4 mg, 177 μmol) was added. Thesolution was stirred for 4 additional hours, when complete consumptionof the starting materials was observed. The reaction was worked up byremoval of the solvent in vacuo and purifying the residue by silica gelchromatography using MeOH—CH₂Cl₂ (10-30%). The product collected fromthis chromatography step was sufficiently pure to be carried on to thenext reaction. A small amount of the product (20 mg) was repurified byRP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 12.9 mg(76%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, 6H,J=7.2 Hz), 3.21 (s, 3H), 3.70 (m, 2H), 4.00 (q, 4H, J=7.2 Hz), 4.81 (s,2H), 6.81 (d, 2H, J=9 Hz), 7.71 (d, 2H, J=9 Hz), 8.40 (br s, 1H), 8.61(s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.4. MS (m/z) 475.2 [M+H]⁺, 597.2[M+Na]⁺.

EXAMPLE 214 Preparation of Representative Compound of Formula231-(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (60 mg, 126 μmol)in dry DMF (0.90 mL) was added trimethylsilyl bromide(bromotrimethylsilane, TMSBr, 130.6 μL, 1,010 μmol) at ambienttemperature. The solution was then heated at 70° C. for 4.0 hours, afterwhich the reaction mixture was allowed to cool to room temperature. Thesolvent volume was reduced to ˜700 μL in vacuo and diluted with H₂O (100μL). This solution was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 26.8 mg (51%) of the desiredcompound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H),3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.79 (d, 2H, J=9 Hz),8.07 (br s, 1H), 8.56 (s, 1H); MS (m/z) 419.2 [M+H]⁺.

EXAMPLE 215 Preparation of Representative Compound of Formula231-(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 4 hours,when diethyl(aminoethyl)phosphonate (43.8 mg, 161 μmol) was added. Thesolution was stirred for 3 additional hours, by which time completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The productcollected from this chromatography step was sufficiently pure to becarried on to the next reaction. A small amount of the product (32 mg)was re-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%)to provide 19 mg (70%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.21 (t, 6H, J=7 Hz), 1.95-2.05 (m, 2H), 3.20 (s, 3H), 3.13-3.22 (m,2H), 3.98 (appt septet, 4H, J=7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J=9 Hz),7.65 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.60 (s, 1H). ³¹P (121.4 MHz,DMSO-d₆) δ 28.9. MS (m/z) 489.2 [M+H]⁺, 511.2 [M+Na]⁺.

EXAMPLE 216 Preparation of Representative Compound of Formula231-(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (61 mg, 125 μmol)in dry DMF (1.00 mL) was added TMSBr (129.0 μL, 999.2 μmol) at ambienttemperature. The solution was then heated at 70° C. for 5.5 hours, whenLCMS analysis demonstrated the reaction to be 90% complete. The reactionmixture was allowed to cool to room temperature and stirred for anadditional 12 hours. The reaction was worked up by removal of thesolvent in vacuo and dissolving the residue in DMF/H₂O (800 μL, 1:1) and1N aqueous NaOH (15 μL). The product was purified by RP HPLC on C₁₈column using H₂O/acetonitrile (2-95%) to provide 29 mg (53%) of thedesired compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25-3.40 (m, 2H), 4.76 (s, 2H), 6.71(br s, 2H), 5.80 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.73 (br s, 2H),8.15 (br s, 1H), 8.56 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.0. MS (m/z)431.3 [M−H]⁻.

EXAMPLE 217 Preparation of Representative Compound of Formula231-(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 mmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 3 hours,when diethyl(aminopropyl)phosphonate (34.9 mg, 122.6 μmol) was added.The solution was stirred for 2 additional hours, whereupon completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The product(65.5 mg) collected from this chromatography step was sufficiently pureto be carried on to the next reaction. A small amount (32.8 mg) wasre-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 23.2 mg (75%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H),3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz),7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); ³¹P (121.4 MHz,DMSO-d₆) δ 31.9; MS (m/z) 503.2 [M+H]⁺.

EXAMPLE 218 Preparation of Representative Compound of Formula231-(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester post silica column chromatography (32.2 mg, 66.2μmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 μmol) atambient temperature. The solution was then heated at 70° C. for 1.0hour, when LCMS analysis demonstrated the reaction to be complete. Thereaction mixture was allowed to cool to room temperature, and water (60μL) and methanol (60 μL) were added. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 11.2 mg (38%) of the desired compound as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25-3.40(m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 8.20(br s, 1H), 8.69 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 26.3. MS (m/z)447.3 [M−H]⁻.

EXAMPLE 219 Preparation of Representative Compound of Formula231-2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}-ethyl)phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomeric mixture at phosphorus]

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL) wereadded diethyl cyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL,474.9 μmol). The solution was stirred at ambient temperature for 3.5hours, when a solution of(S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]-propionic acid ethyl estermono acetic acid salt (57.1 mg, 158.3 μmol; mixture of diastereomers atphosphorus) in DMF (200 μL) was added. The solution was stirred for 1.5additional hours, whereupon complete consumption of the startingmaterials was observed. The solvent was removed in vacuo and the crudematerial was purified by silica gel chromatography using MeOH—CH₂Cl₂(10-30%). A small amount of the product (24.8 mg) was repurified by RPHPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 15.8 mg(65%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.27 (m,3H), 1.32 (d, 2H, J=7.5 Hz), 1.42 (d, 1H, J=7.5 Hz) 2.27 (m, 2H), 3.19(s, 3H), 3.53 (m, 2H), 4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H),6.72 (br s, 1H), 6.81 (d, 2H, J=9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66(d, 2H, J=9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆)δ 26.6, 27.4. MS (m/z) 609.2 [M+H]⁺.

EXAMPLE 220 Preparation of Representative Compound of Formula231-2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}-ethyl)phenoxyphosphinoyloxy]-propionicacid [diastereomeric mixture at phosphorus]

To a solution of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methyl-amino]benzoylamino}ethyl)phenoxyphosphinoyloxy]propionic acid ethyl ester (mixture ofdiastereomers at phosphorus; 40.0 mg, 65.7 μmol) in DMF (0.4 mL),acetonitrile (0.2 mL) and water (0.2 mL) was added aqueous sodiumhydroxide (1 N, 131.4 μL). The solution was stirred at ambienttemperature for 4 hours. The solvents were removed in vacuo and thecrude product was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 23.7 mg (71.3%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (d, 2H, J=6.9 Hz), 1.79 (m, 2H), 3.21(s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H), 6.79 (d, 2H, J=8.7Hz), 7.64 (d, 2H, J=9.7 Hz), 8.25 (br s, 1H), 8.63 (s, 1H); ³¹P (121.4MHz, DMSO-d₆) δ 25.1. MS (m/z) 505.2 [M+H]⁺.

EXAMPLE 221 Preparation of Representative Compound of Formula231-2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomerically pure at phosphorus]

To a solution of4-[(2,4-diaminopteridin-6-ylmethyl)-methyl-amino]benzoic acidhemihydrochloride dihydrate (101.9 mg, 268.9 μmol) in DMF (3.3 mL) wereadded diethyl cyanophosphonate (53.0 μL, 349.5 μmol) and DIEA (138.0 μL,806.7 μmol). The solution was stirred at ambient temperature for 2.5hours, whereupon (S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]-propionicacid ethyl ester mono acetic acid salt (diastereomerically pure atphosphorus; 268.9 μmol) in DMF (500 μL) was added. The solution wasstirred for 30 additional minutes, whereupon complete consumption of thestarting materials was observed. The solvent was removed in vacuo andthe crude material was purified by silica gel chromatography usingMeOH—CH₂Cl₂ (10-30%). A small amount of the product (40.0 mg) wasrepurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 28.7 mg (75.1%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.15 (t, 3H, J=7.2 Hz), 1.44 (d, 3H, J=6.9 Hz), 2.26 (m, 2H), 3.23 (s,3H), 3.51 (m, 2H), 4.09 (q, 2H, J=7.2 Hz), 4.86 (s, 2H), 5.01 (m, 1H),6.81 (d, 2H, J=9.3 Hz), 7.21 (m, 3H), 7.35 (m, 2H), 7.68 (d, 2H, J=9.3Hz), 8.29 (br s, 1H), 8.71 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.6. MS(m/z) 609.2 [M+H]⁺.

EXAMPLE 222 Preparation of Representative Compound of Formula231-2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}-ethyl)-phenoxyphosphinoylamino]propionicacid ethyl ester (mixture of diastereomers at phosphorus)

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (39.6 mg, 104.0 μmol) in DMF (1.2 mL) wereadded diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL,209.4 μmol). The solution was stirred at ambient temperature for 3hours, when (S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acidethyl ester mono acetic acid salt (mixture of diastereomers atphosphorus; 104.0 μmol) in DMF (200 μL) was added. The solution wasstirred for 30 minutes when complete consumption of the startingmaterials was observed. An aliquot (66%) of the reaction was purified bysilica gel chromatography using MeOH—CH₂Cl₂ (10-30%), yielding 27.2 mgof crude product. A small amount of the product (10 mg) was repurifiedby RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 4.2mg (26%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.11 (t, 3H,J=6.9 Hz), 1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51(m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80(d, 2H, J=9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d,2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹P (121.4 MHz, DMSO-d₆) δ29.5, 30.1. MS (m/z) 608.2 [M+H]⁺.

EXAMPLE 223 Preparation of Representative Compound of Formula231-2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6-(diethoxy-phosphoryl)-hexanoicacid

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (63.0 mg, 166.2 μmol) in DMF (2.8 mL) wereadded diethyl cyano phosphonate (30.8 μL, 199.4 μmol) and DIEA (85.8 μL,498.6 μmol). The solution was stirred at ambient temperature for 3.5hours when (L)-2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2μmol) was added. The solution was stirred for 48 additional hours. Thereaction was worked up by removal of the solvent in vacuo and purifyingthe residue by silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). Theproduct (87 mg) collected from this chromatography step was sufficientlypure to be carried on to the next reaction. An aliquot of the product(51.0 mg) was repurified by RP HPLC on C₁₈ column using H₂O/acetonitrile(2-95%) to provide 24.7 mg (44%) of the pure product. ¹H NMR (300 MHz,DMSO-d₆) δ 1.18 (t, 6H, J=6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s,3H), 3.92 (m, 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d,2H, J=9 Hz), 7.73 (d, 2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.56 (s, 1H);³¹P (121.4 MHz, DMSO-d₆) δ 31.8; MS (m/z) 574.3 [M]⁺.

EXAMPLE 224 Preparation of Representative Compound of Formula231-2-{4-[(2,4-Diaminopteridin-6-ylmethyl)methylamino]benzoylamino}-6-(phosphoryl)hexanoicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methylamino]-benzoylamino})-2′(L)-(6′-(phosphonic acid diethyl ester) hexanoic acid) post silicacolumn chromatography (20 mg, 34.6 μmol) in dry DMF (0.60 mL) was addedTMSBr (18.0 μL, 139.2 μmol) at ambient temperature. The solution wasthen heated at 70° C. for 18 hours, after which the reaction mixture wasallowed to cool to room temperature. The solvent was removed in vacuoand dissolved in DMF (400 μL) and water (60 μL). This solution waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 8.9 mg (49%) of the product as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77(s, 2H), 6.62 (br s, 1H), 6.80 (d, 2H, J=8.7 Hz), 7.73 (d, 2H, J=8.7Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS (m/z) 519.2 [M+H]⁺.

EXAMPLE 225 Preparation of Representative Compound of theInvention—2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino)-6′-(monophenyl-phosphonate)hexanoic acid

The ethyl-TMS ester is hydrolyzed under suitable conditions to providethe corresponding acid of the invention.

The intermediate2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester can be prepared asfollows.

a. (L)-2-Cbz-Amino-hexanoic acid-6-phosphonic acid

To a suspension of (L)-2-amino-6-(diethoxyphosphonyl)hexanoic acid (106mg, 396.8 μmol) in dry DMF (2.00 mL) was added TMSBr (307.0 μL, 2,381.0μmol) at ambient temperature. The solution was then heated at 70° C. for2 hours, after which the reaction mixture was allowed to cool to roomtemperature. The solvent was removed in vacuo. The crude material wasdissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzylchloroformate (79.3 μL, 555.5 μmol) was added and stirring at roomtemperature was continued. After 2 hours, the solution was washed withether (2 mL) and the aqueous layer was acidified with aqueous HCl topH 1. The aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganic extracts were dried over sodium sulfate. Filtration andevaporation of solvents yielded a crude product, which was sufficientlypure for further transformations. ¹H NMR (300 MHz, DMSO-d₆) δ 1.42-1.65(m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H), 7.94(s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.5; MS (m/z) 345.6 [M+H]⁺.

b. (L)-2—Aminohexanoic acid 2′ TMS ethyl ester-6-phosphonic acid monophenyl ester

To a solution of (L)-2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3mg, 397.9 μmol) in 2-TMS ethanol (2.5 mL) was added acetyl chloride (50μL). Stirring at room temperature was continued. After 22 hours completeconversion was observed. The solvents were removed in vacuo. The crudematerial was sufficiently pure for the next step.

One half of the crude material (198.9 μmol) was dissolved in toluene(3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 μmol)was added and the reaction mixture was heated at 70° C. (oil bath).After 4 hours, the reaction was cooled to room temperature and thesolvent was removed in vacuo. The crude material was re-dissolved inmethylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0μmol) and DIEA (67.0 μL, 389.0 μmol) in methylene chloride (1.0 mL) wasadded. Stirring at room temperature was continued. After 4 hrs thesolvents were removed in vacuo.

The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) andaqueous sodium hydroxide solution (1N, 0.885 mL) was added. Stirring atroom temperature was continued. After 14 hours the solvent was removedin vacuo to provide the crude phosphonate mono phenyl ester (63.8 mg).This material was dissolved in 2-TMS ethanol (1.0 mL) and acetylchloride (20 μL) was added. Stirring at room temperature was continued.After 22 hours complete conversion to the carboxylate ester wasobserved. The solvents were removed in vacuo. The material wassufficiently pure for the next step.

One half of the crude material (75 μmol) was dissolved in ethanol (1.5mL). Pd/C (5%, 20 mg) was added and the reaction was placed under anatmosphere of hydrogen gas. After 1.5 hours Celite was added and thecrude reaction mixture was filtered through Celite. The solvents wereremoved in vacuo and the crude material was used in the next stepwithout further purification.

c.2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (22.7 mg, 60.0 μmol) in DMF (0.80 mL) wereadded diethyl cyano phosphonate (12.4 μL, 78.0 μmol) and DIEA (31.0 μL,180.0 μmol). The solution was stirred at ambient temperature for onehour when (L)-2-amino-6-monophenoxyphosphonatohexanoic acid 2′ TMS ethylester (70.5 μmol), suspended in DMF (0.2 mL), was added. The solutionwas stirred for 3.5 additional hours. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (5-95%) toprovide 19.4 mg (46%) of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester. ¹H NMR (300 MHz,DMSO-d₆) δ 0.0 (s, 9H), 0.91 (t, 2H, J=8.1 Hz), 1.42-1.53 (m, 4H),1.67-1.76 (m, 4H), 3.24 (s, 3H), 4.10 (t, 2H, J=8.1 Hz), 4.29 (m, 1H),4.86 (s, 2H), 6.81 (d, 2H, J=9 Hz), 7.12 (m, 3H), 7.31 (m, 2H), 7.74 (d,2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.71 (s, 1H); ³¹P (121.4 MHz,DMSO-d₆) δ 26.2; MS (m/z) 695.2 [M]⁺.

EXAMPLE 226 Preparation of Representative Compound of theInvention—2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)methylamino]benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)hexanoic acid

The ethyl-TMS ester is hydrolyzed under suitable conditions to providethe corresponding acid of the invention.

The intermediate2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester can be prepared as follows.

a.2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester

To a solution of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester (14.5 mg, 20.8 μmol,Example 225) in DMF (0.70 mL) was added PyBOP (32.4 mg, 62.4 μmol), DIEA(21.4 mg, 166.4 μmol) and (S) ethyl lactate (19.6 mg, 166.4 μmol). Thereaction mixture was stirred at room temperature for one hour. The crudereaction mixture was purified by RP HPLC on Cl₈ column usingH₂O/acetonitrile (5-95%) to provide 13.5 mg (81%) of the pure product asa mixture of diastereomers at phosphorus (˜4:1). ¹H NMR (300 MHz, CDCl₃)δ 0.0 (s, 9H), 1.02 (t, 2H, J=8.7 Hz), 1.23 (t, 3H, J=9.3 Hz), 1.35 (d,2.4H, J=6.6 Hz), 1.42-1.53 (m, 4.6H), 1.67-1.86 (m, 4H), 3.14 (s, 3H),4.03-4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57(d, 2H, J=7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7.30 (m, 2H), 7.63 (d,2H, J=7.5 Hz), 8.43 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 30.5, 29.2; MS(m/z) 795.2 [M]⁺.

EXAMPLE 227 Preparation of Representative Compound of Formula 253

Representative compounds of the invention can be prepared as illustratedabove. A specific compound of the invention can be prepared as follows.

1-(5-Hydroxy-benzo[b]thiophen-2-yl)-ethanone (prepared as described inKrubsack, A. J. et al., J. Org. Chem., 1975, 40, 3179) is protectedusing a TBS group as described in Greene, T., Protective groups inorganic synthesis, Wiley-Interscience, 1999 to provide compound 227.1(in which X=O and P=TBS). Treatment of compound 227.1 with hydroxylaminein ethanol/pyridine provides oxime 227.2. Reduction of the oxime usingborane pyridine complex yields the hydroxylamine 227.3. Exposure of thehydroxylamine to gaseous HCl followed by phosgene yields a carbamoylchloride which is transformed to the N-hydroxyurea 227.4 with aqueousammonia (U.S. Pat. No. 4,873,259). Protection of the N-hydroxyurea maybe not be necessary, but to avoid subsequent alkylation on this group,the OH is blocked with a benzyl group. Removal of the phenolicprotecting group using TBAF exposes the necessary handle for placementof the pro-drug group. Treatment of the phenol with a base such as NaHor Cs₂CO₃ in solvents such as DMF or THF followed by addition ofphosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986,27, 1477) yields the desired phosphonate pro-drug. Final deblocking ofthe N-hydroxyurea can be achieved by hydrogenolysis conditions asdescribed in U.S. Pat. No. 4,873,259.

EXAMPLE 228 Preparation of Representative Compound of Formula 238

Representative compounds of the invention can be prepared as illustratedabove. A specific compound of the invention can be prepared as follows.

PNP-405 is prepared according to the method of Littler, B. J. et al.,7^(th) International Conference on Organic Process Research andDevelopment, New Orleans, La., Mar. 16-19, 2003. PNP-405 is treated in asolvent such as tetrahydrofuran or dimethylformamide with a base such assodium hydride. When bubbling ceases; diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added, toprovide compound 228.1 as the desired product.

EXAMPLE 229 Preparation of Representative Compound of Formula 236

Representative compounds of the general formula above (where X=O,Z=CH₂OH) can be prepared using procedures similar to those described byLittler, B. J. et al., 7^(th) International Conference on OrganicProcess Research and Development, New Orleans, La., Mar. 16-19, 2003. Aspecific compound of the invention can be prepared as follows.

The starting material, 2-benzyloxyphenylacetic acid (provided byAvocado) can be acylated via the mixed anhydride with the oxazolidinoneshown at 80-85° C., with triethylamine as base. A low-temperaturealkylation with bromoacetonitrile results in the formation of compound229.3 with good diastereomeric ratio. Removal of the chiral auxiliaryunder reductive conditions yields compound 229.4 without racemization.Protection of the resulting alcohol with the trityl group providescompound 229.5. Subsequent pyrrole ring construction as well ascyclo-guanidinylation reaction to prepare the six-membered2-aminopyrimidone ring is performed as described below.

The starting material, 3-(2-Benzyloxy-phenyl)-propionitrile, isavailable by Lewis acid-mediated reaction of phenol with acrylonitrileaccording to U.S. Pat. No. 2,789,995, published in 1954. Formation of3-hydroxy-acrylonitrile 229.7 can be achieved by exposure of 229.6 toLDA and ethyl formate. Condensation of this product with 2-amino-malonicacid diethyl ester in EtOH and sodium acetate yields compound 229.8which undergoes a decarboxylative cyclization in the basic medium ofNaOH and EtOH to provide pyrrole 229.9. The trityl protecting group onthe benzylic alcohol is removed at this stage. Subsequently,guanidinylation reaction using cyanamide provides compound 229.10 which,upon treatment with sodium hydroxide, cyclizes to form the2-aminopyrimidone ring (compound 229.11). Removal of the phenolicprotecting group under hydrogenolysis conditions provides the freephenol, which is used as the attachment site for the pro-drug group. Avariety of linkers may be utilized to attach the phosphonate containingmoiety to the backbone molecule. A particular example in which diethylphosphonomethyltriflate is used as the starting materials is shown.Compound 229.12 is treated in a solvent such as tetrahydrofuran ordimethylformamide with a base such as sodium hydride or cesiumcarbonate. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added, toprovide compound 229.13 as the desired product.

EXAMPLE 230 Preparation of Representative Compound of Formula 235

Representative compounds of the general formula above (where X=O, andZ=CH₂OH) can be prepared from 4-benzyloxyphenylacetic acid (availablefrom Aldrich). The preparation of a specific compound of formula 235 isdescribed below.

Following a similar sequence to that demonstrated in Example 229,intermediate 230.1 can be prepared. Proceeding with the sequence shownin Example 229, 230.1 can be transformed to the desired product.

EXAMPLE 231 Preparation of Representative Compound of Formula 242

Representative compounds of the invention can be prepared as illustratedabove. A specific compound of the invention can be prepared as follows.

Preparation of DADMe-ImmG is reported in Lewandowics A. et al.,Biochemistry, 2003, 42, 6057. The tertiary nitrogen of the ring may notinterfere with the alkylation of the secondary alcohol and in that casedoes not need to be protected, although standard protection anddeprotection protocols as described in Greene, T. Protective groups inorganic synthesis, Wiley-Interscience, 1999 may be used if necessary.Reaction of the primary alcohol 231.1 with base followed by addition ofthe appropriately activated phosphonate yields the protected product.Global deprotection yields the desired phosphonate 231.2.

EXAMPLE 232 Preparation of Representative Compound of Formula 243

Representative compounds of the invention can be prepared as illustratedabove. Preparation of DADMe-ImmG is reported in Lewandowics A. et al.,Biochemistry, 2003, 42, 6057. Blocking of the primary alcohol can beachieved by methods described in Greene, T., Protective groups inorganic synthesis, Wiley-Interscience, 1999. Reaction of the secondaryalcohol in base followed by addition of the appropriately activatedphosphonate yields the protected desired product. Deprotection yieldsthe desired phosphonate. A specific compound of the invention can beprepared as follows.

Specifically, the protected DADMe derivative can be treated with treatedin a solvent such as tetrahydrofuran or dimethylformamide with a basesuch as sodium hydride. When bubbling ceases, diethylphosphonoethylltriflate (prepared according to Tetrahedron Lett., 1986,27, 1477) is added, yielding the desired phosphonate ester. Removal ofthe protecting group can be performed as described in Greene, T.,Protective groups in organic synthesis, Wiley-Interscience, 1999 toprovide the desired phosphonate ester.

EXAMPLE 233 Preparation of Representative Compound of Formula 244

Representative compounds of the invention can be prepared as illustratedabove. O-Alkylation of the oxime can be carried out by mixing the oximeand Cs₂CO₃ (ca. 1:1.2) in DMF at 0° C. for about 30 minutes withstirring. Addition of the triflate (1.2 eq.) followed by deprotection(J. Med. Chem. 2002, 45, 5397) provides the compound.

EXAMPLE 234 Preparation of Representative Compound of Formula 245

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole can be formed using a procedure sililar to thatdescribed in J. Med. Chem. 2002, 45, 5397.

EXAMPLE 235 Preparation of a Representative Compound of Formula 245

Representative compounds of the invention can be prepared as illustratedabove. The hydrazine can be converted to the compound of the inventionusing a procedure similar to that described in Example 234.

EXAMPLES 236-240

The preparation of the following representative compounds of formulae255-257 is illustrated in Examples 236-240.

EXAMPLE 236 Preparation of Representative Compound of Formula 255

Representative compounds of the invention can be prepared as illustratedabove.

EXAMPLE 237 Preparation of Representative Compound of Formula 257

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole can be prepared as described in J. Med. Chem. 1997,40, 1347.

EXAMPLE 238 Preparation of Representative Compound of the Invention

Representative compounds of the invention can be prepared as illustratedabove.

EXAMPLE 239 Preparation of Representative Compound of Formula 256

Representative compounds of the invention can be prepared as illustratedabove.

The intermediate alkyne can be prepared as follows.

EXAMPLE 240 Preparation of Representative Compound of Formula 257

Representative compounds of the invention can be prepared as illustratedabove.

EXAMPLE 241 Preparation of a Representative Compound of Formula 248

Representative compounds of the invention can be prepared as illustratedabove.

EXAMPLE 242 Preparation of Representative Compounds of Formulae 248

Representative compounds of the invention can be prepared as illustratedabove.

EXAMPLE 243 Preparation of Representative Compounds of Formulae 250

Representative compounds of the invention can be prepared as illustratedabove using procedures similar to those described in J. Med. Chem. 1996,39, 4608. Treatment of compound of the invention 243.1 with baseprovides compound 243.2 which is also a compound of the invention.

EXAMPLE 244 Preparation of Representative Compounds of Formulae 250

Representative compounds of the invention can be prepared as illustratedabove. Treatment of compound of the invention 244.1 with base providescompound 244.2 which is also a compound of the invention.

EXAMPLE 245 Preparation of Representative Compounds of Formulae 251

Representative compounds of the invention can be prepared as illustratedabove. The N-alkylation of 6-aryl-3-pyridazinones is described in J.Med. Chem. 1983,26,373.

EXAMPLE 246 Preparation of Representative Compounds of Formulae 251

Representative compounds of the invention (245.1 and 245.2) can beprepared as illustrated above.

EXAMPLE 247 Preparation of Representative Compounds of Formulae 254

Representative compounds of the invention can be prepared as illustratedabove. The synthesis of N-hydroxyureas is described in J. Med. Chem.1997, 40, 1955.

EXAMPLE 248 Preparation of Representative Compounds of Formulae 254

Representative compounds of the invention can be prepared as illustratedabove.

EXAMPLE 249 Preparation of Representative Compounds of Formulae 253

Representative compounds of the invention can be prepared as illustratedabove.

EXAMPLE 250 Preparation of Representative Compounds of Formulae 253

Representative compounds of the invention can be prepared as illustratedabove. The synthesis of substituted benzothiophenes is described in J.Med. Chem. 2000, 43, 690.

EXAMPLE 251 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedabove.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester

A mixture of7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one1A (50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem., 45, 703),diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithiumt-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5hours. The reaction was quenched with 1N HCl. The mixture was pouredinto 5% aqueous lithium chloride, extracted with ethyl acetate, andconcentrated. The residue was purified by chromatography on silica gel,affording[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester 1B (25 mg, 32%); ¹H NMR (300 MHz, CDCl₃) δ1.25(m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (d,2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t,J=6.6 Hz, 1H), 7.83 (s, 1H) ppm.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid and[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monoisopropyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester 1B (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL,1.65 mmol) in acetonitrile was added trimethylsilyl bromide (0.126 mL,1.1 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 4 hours. The reaction was quenched with methanol at 0°C., and the resulting mixture was concentrated. The residue was purifiedby preparative reverse-phase HPLC to afford, after removal of thesolvent,[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid 1C as an oil (17 mg, 83%); ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H),2.06 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.97(s, 2H), 5.20 (s, 2H), 5.47 (t, J=6.6 Hz, 1H) and[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monoisopropyl ester 1D as an oil (2 mg, 7%); ¹H NMR (300 MHz,CD₃OD) δ 1.23 (d, 6H), 1.81 (s, 3H), 2.08 (s, 3H), 3.40 (d, J=6.6 Hz,2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.90 (s, 2H), 4.50 (m, 1H), 5.20 (s,2H), 5.47 (t, J=6.6 Hz, 1H) ppm.

EXAMPLE 252 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester

To a solution of tetramethylmethylene diphosphonate (102 mg, 0.44 mmol)in THF (2.5 mL) was added a THF solution of sodiumbis(trimethysilyl)amide (1.0 M, 0.44 mL). After stirring for 30 minutes,a solution of4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enal2A (30 mg, 0.11 mmol, Pankiewicz et al., J. Med. Chem., 45, 703) in THF(2.5 mL) was added, and stirring was continued for an additional 15minutes. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate. Afterevaporation of solvent, the residue was purified by chromatography onsilica gel eluting with ethyl acetate (50% to 100%)/hexanes, affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester 2B (30 mg, 71%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.80 (s, 3H), 2.04 (s, 3H), 3.45 (d, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.88(d, 6H), 5.20 (s, 3H), 5.55 (m, 1H), 5.95 (m, 1H), 7.05 (m, 1H), 7.65(s, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid

To a solution of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester 2B (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL,1.71 mmol) in acetonitrile was added trimethylsilyl bromide (0.183 mL,1.71 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 1 hour. The reaction was quenched with methanol at 0°C., and the resulting mixture was concentrated. The residue was purifiedby preparative reverse-phase HPLC to afford, after removal of thesolvent,[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid 2C as a solid (13 mg, 65%); ¹H NMR (300 MHz, CD₃OD) δ 1.91 (s, 3H),2.10 (s, 3H), 3.55 (d, J=6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H), 5.6-5.8(m, 2H), 6.9 (m, 1H) ppm.

EXAMPLE 253 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked indichloromethane (10 mL) for 1 hour7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one1A (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) weresequentially added and the mixture was shaken for 1 hour at roomtemperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added andthe mixture was shaken further for 1 hour. The mixture was filtered andthe filtrate was concentrated. The residue was chromatographed on silicagel (0% to 60% ethyl acetate/hexanes) to afford6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one3B as an oil (52 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 1.95 (s, 3H), 2.16(s, 3H), 3.44 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s,2H), 5.68 (t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester

n-Butyl lithium (1.6 M in hexanes, 1 mL) was added to an equal volume ofTHF at −20° C. A solution of diethyl methylphosphonate (220 mg, 1.45mmol) in THF (1 mL) was then added dropwise and the solution was stirredfor 30 minutes. After cooling at −60° C., the solution was transferredvia a cannula to a vial containing copper (I) iodide (276 mg, 1.45mmol), and the resulting mixture was stirred for 1 hour at −30° C. Asolution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one3B (50 mg, 0.15 mmol) in THF (1 mL) was added and the mixture wasallowed to warm to 0° C. for 2 hours before saturated aqueous ammoniumchloride was added. The reaction mixture was acidified with 2 N HCl andextracted with ethyl acetate. The ethyl acetate extract was concentratedand the residue was chromatographed on silica gel (40% to 100% ethylacetate/hexanes), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester 3C as an oil (27 mg, contaminated with the startingdiethyl methylphosphonate); ¹H NMR (300 MHz, CDCl₃) δ 1.32 (m, 6H),1.8-1.9 (m, 5H), 2.18 (s, 3H), 2.25 (m, 2H), 3.42 (d, J=7.2 Hz, 2H),3.78 (s, 3H), 4.15 (m, 4H), 5.21 (s, 2H), 5.24 (t, J=7.2 Hz, 1H), 7.65(s, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester

A mixture of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester 3C (27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL)and water (1 mL) was stirred at 70° C. for 4 hours. After cooling, thereaction solution was acidified with 2 N HCl, mixed with brine, andextracted with ethyl acetate/acetonitrle. The organic extract wasconcentrated and the residue was purified by preparative reverse-phaseHPLC (acetonitrile and 0.1% aqueous CF₃COOH), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester 3D (7 mg, 28%); ¹H NMR (300 MHz, CD₃OD) δ 1.28 (t,J=6.9 Hz, 3H), 1.7-1.9 (m, 5H), 2.20 (s, 3H), 2.2-2.3 (m, 2H), 3.41 (d,J=6.6 Hz, 2H), 3.80 (s, 3H), 4.02 (m, 2H), 5.2-5.3 (m, 3H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid

To a solution of{5-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-sobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (20 mg, 0.039 mmol) in DMF (0.5 mL) and DCM (0.5 mL)was added TMSBr (50.5 μL, 0.39 mmol) followed by 2,6-lutidine (45.3 μL,0.39 mmol). The reaction was allowed to proceed for one hour when it wascomplete, as judged by LCMS. The reaction mixture was quenched with MeOHand concentrated to dryness. The residue was purified by preparativereverse-phase HPLC. The fraction containing the desired product wasconcentrated and treated with 10% TFA/DCM for 5 minutes. Afterconcentration, the residue was purified by preparative reverse-phaseHPLC to provide 7 mg (50%) of[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid as a solid. ¹H NMR (300 MHz, CD₃OD) δ 1.66-1.78 (m, 5H), 2.10 (s,3H), 2.16-2.22 (m, 2H), 3.34 (d, J=7.2 Hz, 2H), 3.72 (s, 3H), 5.16 (s,2H), 5.20 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 31.57 ppm; MS(m/z) 355 [M−H]⁻, 357 [M+H]⁺.

EXAMPLE 254 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-(4-Bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)₄-methyl-hex-4-enoicacid methyl ester

To a cooled (−78° C.) solution of mycophenolic acid methyl ester 4A (138mg, 0.41 mmol) in THF (2.5 mL) was added a THF solution of sodiumbis(trimethysilyl)amide (1.0 M, 0.98 mL). After stirring for 30 minutes,a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL)was added and stirring was continued for 10 minutes. The resultingmixture was warmed to −30° C. and stored at this temperature for 16hours. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate to give, afterevaporation of the solvent, a residue that was purified bychromatography on silica gel eluting with ethyl acetate (0% to40%)/hexanes, affording2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4B (150 mg, 78%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J=6.6 Hz, 2H),3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J=4.8 Hz, 2H), 5.1-5.3 (m, 3H),5.67 (brs, 2H), 7.67 (s, 1H) ppm.

2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

A solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4B (140 mg, 0.30 mmol) and triethylphosphite (600 mg,3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. Themixture was concentrated and chromatographed on silica gel eluting withethyl acetate (60% to 100%)/hexanes, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C as an oil (70 mg, 43%); ¹H NMR (300 MHz, CDCl₃) δ1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.52(s, 3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.

2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg)in a mixture of THF (6 mL) and water (1 mL) was stirred at roomtemperature for 6 hours. The organic solvent was removed and the residuewas partitioned between ethyl acetate and 5% aqueous sodium bicarbonate.The aqueous layer was acidified with 2 N HCl and extracted with ethylacetate. The ethyl acetate extract was concentrated, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid 4D as an oil (30 mg, 100%); ¹H NMR (300 MHz, CDCl₃) δ 1.27 (m, 6H),1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.75 (s, 3H), 4.08(m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45(m, 2H) ppm.

2-[4-(Ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg)in a mixture of methanol (3 mL) and water (1 mL) was stirred at 70° C.for 2 hours. The organic solvent was evaporated and the residueacidified with 2N HCl and extracted with ethyl acetate/acetonitrile. Theorganic extract was concentrated, and the residue was purified bypreparative reverse-phase HPLC (acetonitrile and 0.1% aqueous CF₃COOH),affording2-[4-(ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid 4E as an oil (15 mg, 89%); ¹H NMR (300 MHz, CD₃OD) δ 1.25 (t, J=6.9Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J=6.6 Hz, 2H), 3.77 (s,3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H) ppm.

2-[4-(Dimethoxy-phosphoryl)but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

Under a N₂ atmosphere, a solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (490 mg, 1.05 mmol) in trimethylphosphite (2.5 mL,21.1 mmol) was heated at 120° C. for 1 hour. The reaction was allowed tocool to room temperature. The reaction mixture was worked up by removalof the solvent in vacuo followed by chromatography using EtOAc-hexanesto provide 460 mg (88%) of the product as an oil. ¹H NMR (300 MHz,CDCl₃) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H,J=22 Hz), 2.54 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J=7Hz), 3.57 (s, 3H), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 5.20 (s, 2H),5.20-5.26 (m, 1H), 5.36-5.56 (m, 2H), 7.69 (s, 1H) ppm; ³¹P (121.4 MHz,CDCl₃) δ 30.1 ppm; MS (m/z) 497.2 [M+H]⁺, 519.2 [M+Na]⁺.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (460 mg, 0.927 mmol) in a solution of 1:1:2 of H₂O,MeOH, THF (8 mL) was stirred with LiOH.H₂O (78 mg, 1.86 mmol) at ambienttemperature for 12 hours. A second batch of LiOH.H₂O (40 mg, 0.952 mmol)was added. The reaction mixture was stirred at room temperature foranother 16 hours, after which no further progress was observed. Thereaction was quenched by addition of a saturated aqueous solution ofNH₄Cl. The organic layer was removed in vacuo and the product wasextracted with EtOAc from the aqueous layer, which had been acidified byaddition of 5 drops of 2 N HCl. The product was further purified bychromatography to provide the desired product. ¹H NMR (300 MHz, CDCl₃) δ1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=22 Hz),2.60 (d, 1H, J=22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H, J=7 Hz), 3.72 (d,6H, J=11 Hz) 3.76 (s, 3H), 5.20 (s, 2H), 5.27 (t, 1H, J=6 Hz), 5.36-5.63(m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 30.5 ppm; MS (m/z) 481.2 [M−H]⁻.

2-[4-(2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

To a solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (25 mg, 0.052 mmol) in acetonitrile (2 mL) was added 2,6-lutidine(60 μL, 0.52 mmol) and TMSBr (67 μL, 0.52 mmol). The reaction wasallowed to proceed for 45 minutes when it was completed as judged byLCMS. The reaction mixture was concentrated under reduced pressure andquenched with an aqueous NaOH solution (1 mL). The product was purifiedby RP HPLC (using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA) to provide 14.2 mg (60%) of the product as asolid. ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H), 2.081-2.31 (m, 4H), 2.16(s, 3H), 2.45 (d, 1H, J=22 Hz), 2.47 (d, 1H, J=22 Hz), 2.55-2.63 (m,1H), 3.38 (d, 2H, J=7 Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20-5.36 (m,1H), 5.36-5.56 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 25.4 ppm; MS (m/z)453 [M−H]⁻.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-66-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol)in THF (8.00 mL) was stirred with triphenylphosphine (345 mg, 1.33mmol). To this solution was added diethyl azodicarboxylate (230 μL, 1.33mmol) at 0° C. The mixture was allowed to warm to room temperature andstirred for 16 hours. Additional triphenylphosphine (180 mg, 0.692mmol), trimethylsilylethanol (160 mg, 1.36 mmol), and diethylazodicarboxylate (115 μL, 0.665 mmol) were added and the reactionmixture was stirred for another 1 day at room temperature. The reactionwas worked up by removing the solvents in vacuo and purifying theresidue by silica gel chromatography to provide 192 mg (85%) of theproduct as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 0.05 (s,9H), 0.93-0.96 (m, 2H), 1.20-1.29 (m, 2H), 1.78 (s, 3H), 2.01-2.32 (m,4H), 2.17 (s, 3H), 2.51 (d, 1H, J=22 Hz), 2.58 (d, 1H, J=22 Hz),2.50-2.60 (m, 1H), 3.37 (d, 2H, J=7 Hz), 3.72 (d, 6H, J=11 Hz), 3.76 (s,3H), 4.08 (appt t, 2H, J=8 Hz), 4.30 (appt t, 2H, J=8 Hz), 5.12 (s, 2H),5.15-5.25 (m, 1H), 5.36-5.63 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.3ppm; MS (m/z) 705.3 [M+Na]⁺.

2-[4-(Hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]lmethyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester

A mixture of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) intert-butylamine (2.8 mL, 27 mmol) was heated at 60° C. for 24 hours. Thesolution was allowed to cool to room temperature and concentrated. Theresidue was purified by silica gel column chromatography usingMeOH/CH₂Cl₂ (0-30%) to provide 75 mg of the product as a clear oil. ¹HNMR (300 MHz, CDCl₃) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J=9Hz), 1.23 (appt t, 2H, J=9 Hz), 1.77 (s, 3H), 2.01-2.31 (m, 4H), 2.17(s, 3H), 2.36 (d, 1H, J=22 Hz), 2.38 (d, 1H, J=22 Hz), 2.52 (septet, 1H,J=9 Hz), 3.39 (d, 2H, J=7 Hz), 3.51 (d, 3H, J=11 Hz), 4.01-4.08 (m, 2H),4.30 (dd, 2H, J=8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J=6 Hz),5.33-5.56 (m, 2H), 8.49 (br s, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.1ppm; MS (m/z) 667.4 [M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol) and PyBOP (234mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate(53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperaturefor 1 hour, when complete consumption of the starting materials wasobserved. The reaction was worked up by addition of saturated aqueoussodium chloride and ethyl acetate. The organic layer was separated andwashed with 5% aqueous solution of lithium chloride. The organic layerwas dried in vacuo and the residue was purified by silica gelchromatography using MeOH—CH₂Cl₂ (0-20%) to provide 57 mg (74%) of thedesired product as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 9H),0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s,3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz),3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07(appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61(m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 28.9, 29.9 ppm; MS (m/z) 791.4[M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)₄-methyl-hex-4-enoicacid

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (14 mg, 0.018 mmol) in THF (1 mL)was stirred with a 1M solution of TBAF in THF (55 μL, 0.055 mmol) for 1hour. The reaction mixture was concentrated, acidified with 1N HCl andextracted with EtOAc. The organic layer was washed with brine and dried.The product was purified by silica gel column chromatography EtOH-EtOAc(0-10%). Further purification was performed by dissolving the product inCH₂Cl₂ and passing the compound through a 13 mm Acrodisc syringe filterwith a 0.45 μm Nylon membrane to provide 8 mg (77%) of the product. ¹HNMR (300 MHz, CDCl₃) δ 0.92 (t, 3H, J=7 Hz), 1.30 (d, 3H, J=8 Hz), 1.79(s, 3H), 2.10-2.39 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=8 Hz), 2.65 (d,1H, J=22 Hz), 2.68 (d, 1H, J=22 Hz), 3.38 (d, 2H, J=7 Hz), 3.70 and 3.74(d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J=7 Hz),5.20 (s, 2H), 5.27 (br t, 1H, J=7 Hz), 5.33-5.55 (m, 2H), 7.51-7.56 (m,1H), 7.68-7.74 (m, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.0, 30.1 ppm; MS(m/z) 569.2 [M+H]⁺, 591.3. [M+Na]⁺.

2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) intert-butylamine (1 mL, 9.6 mmol) was heated at 65° C. for 16 hours. Thesolution was allowed to cool to room temperature and concentrated toprovide the crude product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s,9H), 0.04 (s, 9H), 0.86-0.98 (m, 2H), 1.22-1.33 (m, 2H), 1.50 (d, 3H,J=7 Hz), 1.78 (s, 3H), 2.05-2.30 (m, 4H), 2.10 (s, 3H), 2.48-2.63 (m,3H), 3.40 (d, 2H, J=7 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J=9 Hz),4.25-4.33 (m, 2H), 4.75-4.84 (m, 1H), 5.13 (s, 2H), 5.15-5.23 (m, 1H),5.33-5.55 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 28.9 ppm; MS (m/z) 725.3[M−H]⁻.

2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)₄-methyl-hex-4-enoicacid

A solution of crude2-{4-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammoniumfluoride in THF (1M, 54 μL, 0.054 mmol) was stirred with THF (1 mL) for2 hours at ambient temperature, when more tetrabutylammonium fluoride inTHF (54 μL, 0.054 mmol) was added. The reaction was stirred for anadditional 16 hours, by which time the reaction was complete. Thereaction mixture was concentrated in vacuo and the product was purifiedby RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2mm) with eluents of H₂O, 0.1% TFA-CH₃CN, 0.1% TFA to provide the product(8.0 mg) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 1.51 (d, 3H, J=7 Hz),1.79 (s, 3H), 2.05-2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 (m, 3H), 3.38(d, 2H, J=6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21-5.30(m, 1H), 5.33-5.63 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.7 ppm; MS(m/z) 525.2 [M−H]⁻.

2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (20 mg, 0.030 mmol), PyBOP (62.4 mg,0.120 mmol) in DMF (1.0 mL) was stirred with L-alanine ethyl esterhydrochloride (18 mg, 0.12 mmol) and DIEA (26 μL, 0.15 mmol) at ambienttemperature for 1 hour, when complete consumption of the startingmaterials was observed. The reaction was worked up by addition of wateruntil the reaction solution became cloudy. DMF was added dropwise untilthe mixture became clear again. The reaction mixture was filteredthrough Acrodisc (13 mm syringe filter with a 0.45 μm Nylon membrane)and purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80Acolumn (50×21.2 mm), eluting with water and acetonitrile. The fractionscontaining the product were pooled together and concentrated in vacuo toremove the acetonitrile. The remaining solution was saturated withsodium chloride and extracted with EtOAc and acetonitrile to provide 7.2mg of the product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 0.05 (s, 9H),0.923 (appt t, 2H, J=8 Hz), 1.18-1.31 (m, 5H), 1.41 (t, 3H, J=7 Hz),1.78 (s, 3H), 2.03-2.36 (m, 4H), 2.18 (s, 3H), 2.43-2.63 (m, 3H),3.10-3.30 (m, 1H), 3.40 (d, 2H, J=7 Hz), 3.62 and 3.65 (d, 3H, J=11 Hz),3.76 (s, 3H), 4.03-4.12 (m, 2H), 4.20 (dq, 2H, J=2, 7 Hz), 4.29 (appt t,2H, J=8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H), 5.33-5.67 (m, 2H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 30.4, 31.2 ppm; MS (m/z) 790.4 [M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)₄-methyl-hex-4-enoicacid

To a solution of2-{4-[(1-ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (7.2 mg, 9.38 mmol) in THF (1 mL)was added TBAF (40 μL, 1M solution in THF) at room temperature. Thereaction mixture was stirred for 20 minutes, when the starting materialwas completely converted to the desired product as judged by LCMS. Thereaction mixture was dried in vacuo and re-dissolved in DMF. The productwas purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80Acolumn (50×21.2 mm) with eluents of H₂O—CH₃CN. The fractions containingthe desired product were pooled and further purified on Dowex 50WX8-400packed on a 4.5 cm×2 cm column to elute the sodium salt at H₂O-MeOH(1:1), providing 3.2 mg of the desired product. ¹H NMR (300 MHz, CD₃OD)δ 1.26 (dd, 3H, J=4, 7 Hz), 1.37 (t, 3H, J=8 Hz), 1.80 (s, 3H),2.00-2.22 (m, 4H), 2.10 (s, 3H), 2.25-2.60 (m, 3H), 3.37 (d, 2H, J=7Hz), 3.60 and 3.65 (d, 3H, J=11 Hz), 3.74 (s, 3H), 3.83-3.96 (m, 1H),4.18 (q, 2H, J=8 Hz), 5.15 (s, 2H), 5.25-5.42 (m, 2H), 5.55-5.69 (m, 1H)ppm; ³¹P (121.4 MHz, CD₃OD) δ 33.8, 34.2 ppm; MS (m/z) 568.2 [M+H]⁺,590.3 [M+Na]⁺;

6(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-4-methyl-hex-4-enoicacid

To a solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) in THF (1 mL) wasadded TBAF (50 μL, 1M solution in THF) at room temperature. The solutionwas stirred for 16 hours and concentrated. The solution was dried underreduced pressure and re-suspended in DMF (0.8 mL) and water (0.25 mL).The solution was filtered through Acrodisc (13 mm syringe filter with a0.45 μm Nylon membrane) and purified by RP HPLC using a PhenomenexSynergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of H₂O, 0.1%TFA-CH₃CN, 0.1% TFA. The product from the column was subjected to ionexchange chromatography (Sodium salt form of Dowex 50WX8-400) using a2×4.5 cm column eluting with H₂O-MeOH (1:1) to provide 7.5 mg of thedesired product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 1.80 (s, 3H),2.01-2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J=22 Hz), 3.38 (d, 2H, J=7Hz), 3.53 (d, 3H, J=11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J=6Hz), 5.43-5.54 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 23.5 ppm; MS (m/z)469.2 [M+H]⁺, 491.3 [M+Na]⁺.

6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoicacid methyl ester

To a solution of6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (222 mg, 0.66 mmol), triphenylphosphine (260 mg, 0.996mmol), and diethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL)at 0° C. was added a solution of 2-trimethylsilylethanol (142 μL, 0.996mmol) in THF (3 mL). The resulting yellow solution was allowed to warmto room temperature and stirred overnight. The reaction was concentratedto dryness and ether and hexanes were added. Triphenylphosphine oxidewas removed by filtration and the filtrate was concentrated and purifiedby silica gel chromatography to provide 248 mg of the desired product asa colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.18-1.30 (m,2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m, 2H),3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m, 2H),5.13 (s, 2H), 5.12-5.22 (m, 1H) ppm.

[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde

A solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH₂Cl₂ (10 mL)and pyridine (50 μL, 0.618 mmol) was cooled to −70° C. using a dryice/acetone bath according to the procedure of Smith, D. B. et al., J.Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through thereaction via a gas dispersion tube until the reaction became blue incolor (15 minutes). The ozone line was replaced with a stream ofnitrogen and bubbling continued for another 15 minutes, by which timethe blue color had disappeared. To this solution, thiourea (75.7 mg,0.994 mmol) was added in one portion at −70° C., and the cooling bathwas removed. The reaction was allowed to warm to room temperature andstirred for 15 hours. The reaction was worked up by filtration to removesolid thiourea S-dioxide, and then partitioned between CH₂Cl₂ and water.The organic layer was removed. The aqueous layer was washed with CH₂Cl₂one more time, and the organic extracts were combined. The organic layerwas washed with aqueous 1N HCl, saturated NaHCO₃ and brine. The organicextracts were dried in vacuo and the residue was purified to by silicagel chromatography to afford 357 mg (75%) of the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 9H), 1.05-1.15 (m, 2H), 2.15(s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27-4.39 (m, 2H), 5.11 (s,2H), 9.72 (d, 1H, J=1 Hz) ppm.

4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal

[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(70 mg, 0.21 mmol) in toluene (2 mL) was heated at 100° C. with2-(triphenyl-phosphanylidene)-propionaldehyde (72.9 mg, 0.23 mmol)overnight. A second portion of2-(triphenyl-phosphanylidene)-propionaldehyde (33 mg, 0.11 mmol) wasadded and the reaction mixture was heated for an additional day. Afterconcentration, the residue was purified by silica gel chromatography toprovide 54 mg (83%) of the desired product as a pale yellow oil. ¹H NMR(300 MHz, CDCl₃) δ 0.00 (S, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16(s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s,2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H) ppm.

6-(4-Hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)₃H-isobenzofuran-1-one

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution ofCeCl₃ (0.68 mL, MeOH: H₂O, 9:1) was added, followed by LiBH₄ (0.14 mL,0.28 mmol of a 2M solution in THF). The ice bath was removed and thereaction mixture was allowed to warm to room temperature. The reactionmixture was stirred for an additional 40 minutes whereupon TLC indicatedcomplete consumption of starting aldehyde. The reaction was worked up byaddition of aqueous 1N HCl (0.5 mL) and the product was extracted withCH₂Cl₂. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layer was concentrated underreduced pressure and the residue was purified by silica gelchromatography to provide 100 mg (97%) of the product as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81(s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H),4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H) ppm.

6-(2-Hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

To a solution of[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(97 mg, 0.29 mmol) in THF (5 mL) was added an aliquot of a 2 M LiBH₄ inTHF (150 μL, 0.300 mmol). The reaction mixture was stirred at roomtemperature for 1 hour when complete consumption of the startingmaterials was observed by TLC. The reaction mixture was worked up byaddition of an aqueous 1N HCl solution and extraction with EtOAc. Theorganic layer was dried in vacuo and the residue was purified by silicagel chromatography to provide the product. ¹H NMR (300 MHz, CDCl₃) δ0.00 (s, 9H), 1.20 (dd, 2H, J=7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H),2.97 (t, 2H, J=6 Hz), 3.76 (t, 2H, J=6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H,J=7, 8 Hz), 5.08 (s, 2H) ppm.

{2-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester

A mixture of6-(2-hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(79 mg, 0.23 mmol) was heated with bromomethylphosphonic aciddiisopropyl ester (120 mg, 0.46 mmol) in the presence of lithiumt-butoxide (22 mg, 0.27 mmol) in DMF (2 mL) at 70° C. overnight. Thereaction mixture was purified by RP HPLC (acetonitrile and 0.1% aqueousCF₃COOH) to provide the desired product. ¹H NMR (300 MHz, CDCl₃) δ 0.00(s, 9H), 1.13-1.25 (m, 2H), 1.26 (t, 12H, J=6 Hz), 2.12 (s, 3H), 2.98(t, 2H, J=7 Hz), 3.60-3.73 (m, 4H), 3.77 (s, 3H), 4.05-4.16 (m, 2H),4.62-4.74 (m, 2H), 5.07 (s, 2H) ppm; MS (m/z) 539 [M+Na]⁺.

EXAMPLE 255 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-ethoxymethyl]-phosphonicacid

To a solution of{2-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and2,6-lutidine (25 μL, 0.21 mmol) was added trimethylsilyl bromide (27 μL,0.21 mmol) at room temperature. The reaction was allowed to proceed for18 hours when completion of the reaction was indicated by LCMS. Thereaction was quenched by addition of MeOH and concentration. The residuewas purified by RP-HPLC using a C18 column. The collected product wasdissolved in a solution of 10% TFA/CH₂Cl₂ to assure completedeprotection. The reaction mixture was lyophilized to provide thedesired product. ¹H NMR (300 MHz, CD₃OD) δ 2.12 (s, 3H), 2.98 (t, 2H,J=7 Hz), 3.66-3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s, 2H) ppm; MS (m/z) 331[M−H]⁻.

EXAMPLE 256 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked indichloromethane (10 mL) for 1 hour7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one(100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) wereadded sequentially and the mixture was shaken for 1 hour at roomtemperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added andthe mixture was shaken further for 1 hour The mixture was filtered andthe filtrate was concentrated. The residue was chromatographed on silicagel (0% to 60% ethyl acetate/hexanes) to afford6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-oneas an oil (52 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 1.95 (s, 3H), 2.16 (s,3H), 3.44 (d, J=7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68(t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester

A solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(33 mg, 0.097 mmol) in trimethylphosphite (1.0 mL, 8.5 mmol) was heatedto 100° C. for 1 hour, whereupon complete reaction was indicated byLCMS. The reaction was worked up by removal of the excess reagent underreduced pressure and the residue was purified by silica gelchromatography using EtOAc-hexanes (20-100%) to provide 20 mg (60%) ofthe desired product. ¹H NMR (300 MHz, CDCl₃) δ 1.90 (s, 3H), 2.09 (s,3H), 2.48 (d, 2H, J=22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J=11 Hz),3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H) ppm;MS (m/z) 371 [M+H]⁺.

EXAMPLE 257 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester (18 mg, 0.049 mmol) in acetonitrile (2 mL) was addedTMSBr (63 μL, 0.49 mmol) and 2,6-lutidine (85 μL, 0.73 mmol) at 0° C.The reaction solution was allowed to warm to room temperature andstirred for 2 hours when completion of the reaction was observed byLCMS. The reaction was cooled to 0° C. and quenched by the addition ofMeOH. The reaction mixture was concentrated under reduced pressure andthe residue was purified by RP HPLC using a C18 column with a gradientof H₂O-acetonitrile (5-0%) over 20 minutes to provide 12.2 mg (73%) ofthe product. ¹H NMR (300 MHz, CD₃OD) δ 1.95 (s, 3H), 2.15 (s, 3H), 2.48(d, 2H, J=22 Hz), 3.44 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.24 (s, 2H), 5.38(q, 1H, J=7 Hz), 6.87 (br s, 1H) ppm; MS (m/z) 341 [M−H]⁻.

EXAMPLE 258 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester and[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid (49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol)was added dicyclohexyl carbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg,0.065 mmol) in DMF (0.6 mL), slowly at 0° C. The reaction was allowed towarm to room temperature and heated to 140° C. for 10 hours. Aftercooling to room temperature the mixture was filtered and extracted withaqueous 1N NaOH solution. The aqueous layer was acidified with aqueous1N HCl and extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated to dryness. The residue was purified by RP HPLC toprovide 18.5 mg of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (major product, Example 8) as a pale yellow solidand 4.1 mg of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester (minor product) also as a pale yellow solid. Majorproduct: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d,2H, J=7 Hz), 3.70 (d, 2H, J=8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s,2H), 5.52 (t, 1H, J=8 Hz), 7.10-7.21 (m, 3H), 7.30 (t, 2H, J=8 Hz) ppm;³¹P (121.4 MHz, CD₃OD) δ 17.3 ppm; MS (m/z) 449.0 [M+H]⁺, 471.2 [M+Na]⁺.Minor product: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.15 (s, 3H),3.47 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.98-4.06 (m, 4H), 5.25 (s, 2H),5.50-5.61 (m, 1H), 7.10-7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; ³¹P (121.4MHz, CD₃OD) δ 16.3 ppm; MS (m/z) 525.2 [M+H]⁺, 547.2 [M+Na]⁺.

EXAMPLE 259 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (18.5 mg, 0.040 mmol) and ethyl (S)-(−)-lactate(47 μL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060mmol). The solution was stirred at room temperature for 1 hour, when anadditional portion of PyBOP (21 mg, 0.040 mmol) was added. The solutionwas stirred for another hour and concentrated. The residue was purifiedby HPLC to provide 7.5 mg of the desired product as a clear oil. ¹H NMR(300 MHz, CD₃OD) δ 1.22 and 1.25 (t, 3H, J=7 Hz), 1.42 and 1.50 (d, 3H,J=7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.78(s, 3H), 3.89 (d, 1H, J=8 Hz), 3.93-4.02 (m, 3H), 4.10-4.22 (m, 2H),4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15-7.27 (m, 3H),7.33-7.41 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 18.9, 20.3 ppm(diastereomers at phosphorus); MS (m/z) 549.2 [M+H]⁺, 571.3 [M+Na]⁺.

EXAMPLE 260 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (20 mg, 0.045 mmol) and L-alanine ethyl esterhydrochloride (68.5 mg, 0.45 mmol) in pyridine (1.0 mL) was added PyBOP(70 mg, 0.114 mmol). After stirring overnight, the mixture wasconcentrated and the residue purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 3.6 mg ofthe product as a colorless gel. ¹H NMR (300 MHz, CD₃OD) δ 1.17-1.3 (m,6H), 1.8-1.9 (m, 3H), 2.16 (s, 3H), 3.17 (m, 1H), 3.47 (d, 2H), 3.72-3.8(m, 5H), 3.92-4.2 (m, 4H), 5.25 (s, 2H), 5.54 (m, 1H), 7.18 (m, 3H),7.33 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 24.1, 25.0 ppm (diastereomersat phosphorus); MS (m/z) 546.2 [M−H]⁺.

EXAMPLE 261 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monomethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester (53 mg, 0.1 mmol) in methanol (0.5 mL) was added anaqueous solution of 1N NaOH (300 μL). After stirring overnight, themixture was concentrated and the residue purified by RP HPLC using a C18column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA toprovide 5 mg of the product as a colorless gel, together with thephosphonic acid monophenyl ester (7 mg) and the phosphonic acid dimethylester (14.5 mg). ¹H NMR (300 MHz, CD₃OD) δ 1.84 (s, 3H), 2.16 (s, 3H),3.47 (d, 2H, J=7 Hz), 3.6 (d, 2H, J=12 Hz), 3.75 (d, 3H, J=11 Hz), 3.79(s, 3H), 3.94 (s, 2H), 5.26 (s, 2H), 5.53 (t, 1H, J=7 Hz) ppm; ³¹P(121.4 MHz, CD₃OD) δ 21.5 ppm; MS (m/z) 385.2 [M−H]⁺, 387.1 [M+H]⁺.

EXAMPLE 262 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(84 mg, 0.22 mmol), (2-amino-ethyl)-phosphonic acid diethyl esteroxalate (91 mg, 0.33 mmol), and sodium triacetoxyborohydride (93 mg,0.44 mmol) in DMF (1.5 mL) was added acetic acid (60 μL, 1.0 mmol) atroom temperature. The solution was stirred for 2 days when it wasquenched by addition of saturated aqueous sodium bicarbonate solutionand EtOAc. The organic layer was separated and concentrated underreduced pressure. The residue was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 115mg (96%) of the product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s,9H), 1.16-1.27 (m, 2H), 1.34 (t, 6H, J=7 Hz), 1.94 (s, 3H), 2.18 (s,3H), 2.20-2.31 (m, 2H), 3.13-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.54(s, 2H), 3.78 (s, 3H), 4.14 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13(s, 2H), 5.65 (t, 1H, J=7 Hz), 6.23 (br s, 2H) ppm; ³¹P (121.4 MHz,CDCl₃) δ 27.8 ppm; MS (m/z) 542.3 [M+H]⁺, 564.2 [M+Na]⁺.

{2-[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphonicacid

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (30 mg, 0.055 mmol), TMSBr (72 mL, 0.55 mmol), and2,6-lutidine (64 μL, 0.55 mmol) was stirred in CH₂Cl₂ (1 mL) and DMF(0.5 mL) for 1 hour at ambient temperature. The reaction mixture waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 7.8 mg of the product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.96 (s, 3H), 1.95-2.07 (m, 2H), 2.16(s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.57 (s, 2H), 3.81 (s,3H), 5.25 (s, 2H), 5.73 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CD₃OD) δ20.2 ppm; ¹⁹F NMR (282.6 MHz, CD₃OD) δ −74.0 ppm; MS (m/z) 386.3 [M+H]⁺.

EXAMPLE 263 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (45 mg, 0.092 mmol) in CH₂Cl₂ (0.5 mL) was stirredwith methanesulfonyl chloride (21 μL, 0.28 mmol) and pyridine (45 μL,0.55 mmol) at ambient temperature overnight. The reaction was quenchedby addition of 2 drops of water. The reaction mixture was concentratedand purified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 36 mg of the product (63%) as aclear gel. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s, 9H), 1.18-1.29 (m, 2H),1.29 (t, 6H, J=7 Hz), 1.85 (s, 3H), 2.00-2.13 (m, 2H), 2.19 (s, 3H),2.85 (s, 3H), 3.32-3.43 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.69 (s, 2H),3.79 (s, 3H), 4.05 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H),5.45 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CD₃Cl) δ 27.5 ppm; MS (m/z)642.2 [M+Na]⁺.

(2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-methanesulfonyl-amino}-ethyl)-phosphonicacid

A solution of[2-(methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (18 mg, 0.029 mmol) in acetonitrile (0.5 mL) wasstirred with TMSBr (38 μL, 0.29 mmol) and 2,6-lutidine (34 μL, 0.29mmol) for 2 hours at room temperature. The reaction was worked up byaddition of EtOAc and aqueous 1N HCl. The organic layer was washed withbrine and the solvent was removed in vacuo. The residue was suspended ina solution of 10% TFA-CH₂Cl₂ for 10 minutes before it was dried toprovide 9.9 mg of the desired product (73%) as a white solid. ¹H NMR(300 MHz, DMSO-d6) δ 1.76 (s, 3H), 1.76-1.88 (m, 2H), 2.10 (s, 3H), 2.87(s, 3H), 3.24-3.35 (m, 2H), 3.39 (d, 2H, J=7 Hz), 3.65 (s, 2H), 3.75 (s,3H), 5.22 (s, 2H), 5.41-5.48 (m, 1H) ppm; ³¹P (121.4 MHz, DMSO-d₆) δ21.4 ppm; MS (m/z) 464.1 [M+H]⁺.

EXAMPLE 264 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

To a solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (32 mg, 0.059 mmol) in acetic acid (0.5 mL) was addedacetic anhydride (0.5 mL). The solution was stirred at room temperaturefor 90 minutes when it was quenched by addition of 2 drops of water. Thesolution was dried in vacuo and the residue was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 28 mg of the product (81%) as a clear gel. The NMR dataof this compound shows two rotamers in a ratio of 70:30. ¹H NMR (300MHz, CDCl₃) δ 0.05 (s, 9H), 1.17-1.27 (m, 2H), 1.30 and 1.31 (t, 6H, J=7Hz), 1.70-1.79 (m, 2H), 1.76 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H),3.40-3.52 (m, 2H), 3.46 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.79 and 3.93 (s,3H), 4.07 (pent, 4H, J=7 Hz), 4.27-4.35 (m, 2H), 5.13 (s, 2H), 5.22-5.30(m, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.5 and 28.9 ppm; MS (m/z) 584.1[M+H]⁺, 606.2 [M+Na]⁺.

(2-{Acetyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

To a solution of[2-(acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (14 mg, 0.024 mmol) in acetonitrile (0.5 mL) wasadded TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24 mmol). Thesolution was stirred at room temperature for 1 hour. The reaction wasquenched by addition of methanol and aqueous 1N HCl. The product wasextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄ and concentrated in vacuo. The product was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 5.4 mg of the product (53%) as a white solid. The NMRdata of this compound shows two rotamers. ¹H NMR (300 MHz, CDCl₃) δ 1.67and 1.73 (s, 3H), 1.85-2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H),3.75 (s, 3H), 3.76 (br s, 2H), 5.17 (s, 2H), 5.31 (br s, 1H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 27.5 and 28.8 ppm; MS (m/z) 428.2 [M+H]⁺, 450.2[M+Na]⁺.

EXAMPLE 265 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Benzyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) was stirredwith acetic acid (15.7 μL, 0.28 mmol) in DMF (0.5 mL) at roomtemperature over night. The reaction was quenched with a 10% aqueousNa₂CO₃ solution and the product was extracted with EtOAc. The organiclayer was dried and concentrated under reduced pressure. The product waspurified purified by RP HPLC using a C18 column with a gradient of H₂O,0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product (43%) asa clear gel. ¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H),1.24 (t, 6H, J=7 Hz), 1.86 (s, 3H), 1.88-2.02 (m, 2H), 2.16 (s, 3H),2.65-2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J=7 Hz), 3.76 (s, 3H),4.00 (pent, 4H, J=7 Hz), 4.25-4.34 (m, 2H), 5.11 (s, 2H), 5.34-5.43 (m,1H), 7.18-7.33 (m, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 30.9 ppm; MS (m/z)632.4 [M+H]⁺, 654.3 [M+Na]⁺.

(2-{Benzyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (15 mg, 0.024 mmol) in acetonitrile (0.5 mL) wastreated with TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24mmol). The solution was stirred at ambient temperature for 1 hour, whenit was quenched with methanol. The solvent was removed under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 11 mg ofthe product (93%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.89 (s,3H), 2.03-2.15 (m, 2H), 2.14 (s, 3H), 3.30-3.47 (m, 2H), 3.50 (br s,2H), 3.62 (br s, 2H), 3.79 (s, 3H), 4.28 (s, 2H), 5.23 (s, 2H), 5.76 (brs, 1H), 7.46 (br s, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 20.1 ppm; MS (m/z)476.3 [M+H]⁺, 498.3 [M+Na]⁺.

EXAMPLE 266 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

To a solution of(2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (74 mg, 0.14 mmol) in formic acid (1 mL) was addedformic anhydride (1 mL) and the solution was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated and the crude productcarried onto the next step. The NMR data of this compound shows tworotamers with the ratio of 70:30. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s,9H), 1.18-1.28 (m, 2H), 1.28 and 1.30 (t, 6H, J=7 Hz), 1.74 (s, 3H),1.84-2.08 (m, 2H), 2.19 (s, 3H), 3.34-3.45 (m, 2H), 3.47 (d, 2H, J=7Hz), 3.72 and 3.87 (s, 2H), 3.78 and 3.79 (s, 3H), 4.06 and 4.07 (pent,4H, J=7 Hz), 4.26-4.37 (m, 2H), 5.13 (s, 2H), 5.30-5.46 (m, 1H), 8.03and 8.19 (s, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.5 and 28.1 ppm; MS(m/z) 570.1 [M+H]⁺, 592.2 [M+Na]⁺.

(2-{Formyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

To a solution of crude[2-(formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (78 mg, 0.14 mmol) in acetonitrile (1 mL) was addedTMSBr (177 μl, 1.4 mmol) and 2,6-lutidine (163 μL, 1.4 mmol). Thesolution was stirred at room temperature for 1 hour when it was quenchedby addition of methanol and 1N aqueous HCl. The product was extractedwith EtOAc and purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 29 mg of the product asa white solid. The NMR data of this compound shows two rotamers with theratio of approximately 70:30. ¹H NMR (300 MHz, CD₃OD) δ 1.62 and 1.64(s, 3H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 3.38-3.55 (m, 4H), 3.78 (s,3H), 3.80 and 3.91 (s, 2H), 5.22 (s, 2H), 5.39-5.52 (m, 1H), 8.03 and8.18 (s, 1H) ppm; MS (m/z) 414.2 [M+H]⁺, 436.2 [M+Na]⁺.

EXAMPLE 267 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

({4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonicacid diethyl ester

To a solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(500 mg, 1.33 mmol), (2-aminomethyl)phosphonic acid diethyl esteroxalate (376 mg, 1.46 mmol), sodium triacetoxyborohydride (563 mg, 2.66mmol) in DMF (10 mL) was added acetic acid (380 μL, 6.65 mmol) at roomtemperature. The solution was stirred overnight when it was quenched byaddition of saturated aqueous sodium bicarbonate solution and EtOAc. Theorganic layer was separated and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to provide 500 mg(71%) of the product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H),1.13-1.23 (m, 2H), 1.25 and 1.27 (t, 6H, J=7 Hz), 1.65-1.75 (m, 2H),1.77 (s, 3H), 2.13 (s, 3H), 2.80 (s, 1H), 3.14 (s, 2H), 3.41 (d, 2H, J=7Hz), 3.73 (s, 3H), 4.08 and 4.09 (pent, 4H, J=7 Hz), 4.20-4.30 (m, 2H),5.08 (s, 2H), 5.30 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 26.5ppm; MS (m/z) 528.1 [M+H]⁺, 550.2 [M+Na]⁺.

{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-methyl}-phosphonicacid

To a solution of({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonicacid diethyl ester (20 mg, 0.038 mmol) in DMF (0.5 mL) was added TMSBr(49 μL, 0.38 mmol) and 2,6-lutidine (44 μL, 0.38 mmol). The solution wasstirred at room temperature for 1 hour when it was quenched by additionof methanol. The product was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.6 mg ofthe product as a white solid. ¹H NMR (300 MHz, CD₃OD and CDCl₃) δ 1.93(s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J=11 Hz), 3.42-3.53 (m, 2H), 3.60(s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s, 1H) ppm; ³¹P (121.4MHz, CDCl₃) δ 8.5 ppm; MS (m/z) 372.2 [M+H]⁺, 743.2 [2M+H]⁺.

EXAMPLE 268 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-({2-[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl]-phenoxy-phosphinoyloxy)-propionicacid ethyl ester

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(188 mg, 0.5 mmol) was stirred with2-[(2-aminoethyl)phenoxy-phosphinoyloxy]-propionic acid ethyl esteracetic acid salt (315.8 mg, 0.75 mmol) in CH₂Cl₂ (3 mL) for 2 hours atambient temperature. Sodium triacetoxyborohydride (159 mg, 0.75 mmol)was added to the solution and the reaction was allowed to proceed for 1hour. The reaction was quenched by addition of a saturated aqueoussolution of NaHCO₃ and the product was extracted with EtOAc. The organiclayer was removed under reduced pressure and the residue was resuspendedin a 10% TFA/CH₂Cl₂ for 1 hour. The reaction mixture was concentratedand the product was purified by RP HPLC using a C18 column with agradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 198 mg ofthe product as a white solid. The NMR data of this compound shows twodiastereomers at phosphorus in a ratio of approximately 45:55. ¹H NMR(300 MHz, CD₃OD) δ 1.23 and 1.24 (t, 3H, J=7 Hz), 1.38 and 1.52 (d, 3H,J=7 Hz), 1.97 and 1.98 (s, 3H), 2.14 (s, 3H), 2.44-2.66 (m, 2H),3.31-3.48 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.66 (d, 2H, J=5 Hz), 3.80 (s,3H), 4.10-4.27 (m, 2H), 4.90-5.10 (m, 1H), 5.20 (s, 2H), 5.73-5.82 (m,1H), 7.15-7.27 (m, 3H), 7.35-7.45 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ22.6, 24.3 ppm; MS (m/z) 561.9 [M+H]⁺.

EXAMPLE 269 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-[Hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionicacid ethyl ester

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(38 mg, 0.1 mmol) was stirred with2-[(2-aminoethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl esteracetic acid (63 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) for 2 hours at ambienttemperature. Sodium triacetoxyborohydride (32 mg, 0.15 mmol) was addedto the solution and the reaction was allowed to proceed for 1 hour. Thereaction was quenched by addition of a saturated aqueous solution ofNaHCO₃ and the product was extracted with EtOAc. The organic layer wasremoved under reduced pressure and the residue was re-suspended in 10%TFA/CH₂Cl₂ for 1 hour. The reaction mixture was concentrated and theproduct was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product(154-2). ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.15-1.24 (m, 2H), 1.26(t, 3H, J=7 Hz), 1.48 (d, 3H, J=7 Hz), 1.93 (s, 3H), 2.10-2.25 (m, 2H),2.18 (s, 3H), 3.10-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.48-3.61 (m,2H), 3.77 (s, 3H), 4.04-4.21 (m, 2H), 4.29-4.40 (m, 2H), 4.81-4.92 (m,1H), 5.13 (s, 2H), 5.64 (t, 1H, J=7 Hz), 8.70-9.11 (m, 3H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 21.9 ppm; MS (m/z) 586.3 [M+H]⁺, 1171.4 [2M+H]⁺.

2-(Hydroxy-{2-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphinoyloxy)-propionicacid

A solution of2-[hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionicacid ethyl ester (15 mg, 0.026 mmol) in 10% TFA-CH₂Cl₂ (1 mL) wasstirred at ambient temperature for 10 minutes. The reaction was workedup by removal of the solvent. The residue was dissolved in THF (0.5 mL)and water (0.4 mL) and 1N aqueous NaOH solution (0.1 mL) was added. Thesolution was stirred at room temperature for 20 minutes when it wasacidified with 1N aqueous HCl solution. The resulting solution waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 6.8 mg of the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 1.38 (d, 3H, J=7 Hz), 1.91 (s, 3H),2.13 (s, 3H), 2.12-2.28 (m, 2H), 3.12-3.33 (m, 2H), 3.41 (d, 2H, J=6Hz), 3.56 (br s, 2H), 3.75 (s, 3H), 4.71-4.88 (m, 1H), 5.16 (s, 2H),5.58-5.71 (m, 1H), 7.88 (br s, 3H), 8.60 (br s, 1H), 8.78 (br s, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.0 ppm; MS (m/z) 458.3 [M+H]⁺, 480.3[M+Na]⁺.

EXAMPLE 270 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of diethyl cyanomethylphosphonate (241 mg, 1.38 mmol) inTHF (1 mL) was added a THF solution of sodium bis(trimethysilyl)amide(1.0 M, 1.13 mL, 1.15 mmol). After stirring for 30 minutes, the solutionwas added dropwise to a solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(100 mg, 0.23 mmol) in THF (1 mL). The resulting mixture was allowed tostir at room temperature for one hour before saturated aqueous ammoniumchloride was added. The reaction mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated to dryness. The residue was purified by silica gel columnchromatography, affording 110 mg (90%) of the desired product. ¹H NMR(300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.24 (dd, J=7, 8 Hz, 2H), 1.36 (t, 6H),1.86 (s, 3H), 2.17 (s, 3H), 2.43-2.57 (m, 2H), 3.04-3.17 (m, 1H), 3.47(d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.44(t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 18.18 ppm; MS (m/z) 560[M+Na]⁺.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (25 mg, 0.047 mmol) was dissolved in a solution of10% TFA/CH₂Cl₂ (5 mL) and stirred at room temperature for 2 hours. Thereaction mixture was dried under reduced pressure and the product waspurified by RP-HPLC to provide 16 mg (80%) of the desired product as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 1.38 (t, 6H), 1.86 (s, 3H), 2.15(s, 3H), 2.40-2.58 (m, 2H), 3.01-3.14 (m, 1H), 3.45 (d, J=7.2 Hz, 2H),3.79 (s, 3H), 4.18-4.30 (m, 4H), 5.21 (s, 2H), 5.48 (t, J=7.2 Hz, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 18.09 ppm; MS (m/z) 436 [M−H]⁻, 438[M+H]⁺.

EXAMPLE 271 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (35 mg, 0.065 mmol) in acetonitrile (2 mL) was addedTMSBr (180 μL, 1.38 mmol) and 2,6-lutidine (160 μL, 1.38 mmol). Thereaction solution was allowed stir at room temperature for one hourbefore quenching with MeOH. The reaction mixture was dried under reducedpressure and the residue was purified by RP HPLC using a C 18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg(60%) of the desired product. ¹H NMR (300 MHz, CD₃OD) δ 1.86 (s,3H),2.15 (s, 3H), 2.38-2.57 (m, 2H), 3.17-3.28 (m, 1H), 3.44 (d, J=7.2 Hz,2H), 3.80 (s, 3H), 5.25 (s, 2H), 5.47 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4MHz, CD₃OD) δ 15.28 ppm; MS (m/z) 380 [M−H]⁻, 382 [M+H]⁺.

EXAMPLE 272 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of{(1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL) was added sodiumbis(trimethysilyl)amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for20 minutes, iodomethane (52 μL, 0.84 mmol) was added dropwise and theresulting mixture was allowed to stir at room temperature for 2 hours.The reaction mixture was quenched with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The organic layer was driedover sodium sulfate and concentrated to dryness. The residue waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to afford 6.6 mg (23%) of the desiredproduct. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.16 (dd, J=7, 8 Hz,2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s,3H), 2.17 (s, 3H), 2.23 (m,1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H),5.08 (s, 2H), 5.28 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.26ppm; MS (m/z) 574 [M+Na]⁺.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-1,3-dimethyl-pent-3-enyl]-phosphonicacid

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonicacid diethyl ester (18 mg, 0.04 mmol) in DMF (0.5 mL) and DCM (0.5 mL)was added TMSBr (51 μL, 0.4 mmol) and 2,6-lutidine (46 μL, 0.4 mmol).The reaction solution was allowed stir at room temperature overnightbefore quenching with MeOH. The reaction mixture was dried under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 4.5 mg(33%) of the desired product. ¹H NMR (300 MHz, CD₃OD) δ 1.37 (d, 3H),1.87 (s, 3H), 2.13 (s, 3H), 2.26 (m, 1H), 2.64 (m, 1H), 3.39 (m, 2H),3.75 (s, 3H), 5.18 (s, 2H), 5.34 (m, 1H) ppm; ³¹P (121.4 MHz, CD₃OD) δ21.47 ppm; MS (m/z) 422 [M−H]⁻, 424 [M+H]⁺.

EXAMPLE 273 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-Ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal

A solution of[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(1.5 g, 4.46 mmol) in toluene (14 mL) was heated at 100° C. with2-(triphenyl-phosphanylidene)-butyraldehyde (1.68 g, 5.35 mmol)overnight. A second portion of2-(triphenyl-phosphanylidene)-butyraldehyde (495 mg, 1.49 mmol) wasadded and the reaction mixture was heated for an additional day. Afterconcentration, the residue was purified by silica gel chromatography toprovide 1.3 g (83%) of the desired product as oil. ¹H NMR (300 MHz,CDCl₃) δ 0.01 (s, 9H), 1.03 (t, 3H), 1.10-1.21 (m, 2H), 2.15 (s, 3H),2.15-2.44 (m, 2H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.31-4.36 (m, 2H),5.10 (s, 2H), 6.34-6.38 (m, 1H), 9.28 (s, 1H) ppm.

6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

A solution of2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(1.3 g, 3.30 mmol) in methanol (10 mL) and THF (10 mL) was cooled to 0°C. A solution of CeCl₃ (8.25 mL, 0.4M, MeOH: H₂O, 9:1) was added,followed by LiBH₄ (1.66 mL, 3.30 mmol of a 2M solution in THF). The icebath was removed and the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was stirred for an additional 40minutes, whereupon TLC indicated complete consumption of startingaldehyde. The reaction was worked up by addition of aqueous 1N HCl andthe product was extracted with EtOAc. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and brine. The organiclayer was concentrated under reduced pressure and the residue waspurified by silica gel chromatography to provide 948 mg (73%) of theproduct as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.07(t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.13 (s, 3H), 2.38-2.50 (m, 2H), 3.77(s, 3H), 3.99 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.34 (t,J=7.2 Hz, 1H) ppm.

6-(3-Bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.66 g) was soaked indichloromethane (6 mL) for 1 hour6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(260 mg, 0.66 mmol) and carbon tetrabromide (657 mg, 1.98 mmol) wereadded sequentially and the mixture was shaken for 1 hour at roomtemperature. The mixture was filtered and the filtrate was concentrated.The residue was purified by silica gel chromatography to provide 233 mg(77%) of the product as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 0.00(s, 9H), 1.08 (t,3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.14 (s, 3H), 2.35-2.43(m, 2H), 3.44 (d, J=7.2, 2H), 3.73 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H,J=7, 8 Hz), 5.08 (s, 2H), 5.53 (t, J=7.2 Hz, 1H) ppm.

[2-Ethyl-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonicacid

A solution of6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(230 mg, 0.5 mmol) in trimethylphosphite (1.5 mL, 12.75 mmol) was heatedto 100° C. for 4 hours. The reaction was worked up by removal of excesstrimethylphosphite under reduced pressure. The residue was dissolved inacetonitrile (1 mL) and TMSBr (646 μL, 5.0 mmol) and 2,6-lutidine (580μL, 5.0 mmol) were added at 0° C. The reaction solution was allowed towarm to room temperature and stirred for 4 hours. The reaction wascooled to 0° C. and quenched with addition of MeOH. The reaction mixturewas dried under reduced pressure and the residue was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 77 mg (58%) of the product. ¹H NMR (300 MHz, CD₃OD) δ1.08 (t, 3H), 2.16 (s, 3H), 2.43 (m, 2H), 2.48 (d, 2H, J=22 Hz), 3.46(t, 2H, J=6 Hz), 3.79 (s, 3H), 5.25 (s, 2H), 5.38 (q, 1H, J=7 Hz) ppm.;³¹P (121.4 MHz, CD₃OD) δ 25.65 ppm.; MS (m/z) 355 [M−H]⁻, 357 [M+H]⁺.

EXAMPLE 274 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of diethyl cyanomethylphosphonate (233 mg, 1.32 mmol) inTHF (1 mL) was added a THF solution of sodium bis(trimethysilyl)amide(1.0 M, 1.21 mL, 1.21 mmol). After stirring for 30 minutes, the solutionwas added dropwise to a solution of6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(100 mg, 0.22 mmol) in THF (1 mL). The resulting mixture was allowed tostir at room temperature overnight before saturated aqueous ammoniumchloride was added. The reaction mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated to dryness. The residue was purified by preparativereverse-phase HPLC, affording 51 mg (42%) of the desired product.

¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.07 (t,3H), 1.24 (dd, 2H, J=7,8 Hz), 1.36 (t, 6H), 2.12 (m, 1H), 2.18 (s, 3H), 2.35-2.47 (m, 2H), 2.67(m,1H), 3.00-3.14 (m, 1H), 3.44 (d, J=7.2, 2H), 3.79 (s, 3H), 4.12-4.37(m, 6H), 5.13 (s, 2H), 5.38 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz,CDCl₃) δ 18.26 ppm; MS (m/z) 574 [M+Na]⁺.

[1-Cyano-3-ethyl-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-pent-3-enyl]-phosphonicacid

{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonicacid diethyl ester (19.5 mg, 0.035 mmol) was dissolved in a solution of10% TFA/CH₂Cl₂ (2 mL) and stirred at room temperature for 10 minutes.The reaction mixture was dried under reduced pressure and purified byRP-HPLC to provide 9.5 mg (61%) of the desired product. This materialwas dissolved in DMF (0.5 mL) and DCM (0.5 mL) and TMSBr (27 μL, 0.2mmol) and 2,6-lutidine (23 μL, 0.2 mmol) were added. The reactionsolution was allowed stir at room temperature overnight before quenchingwith MeOH. The reaction mixture was dried under reduced pressure and theresidue was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.1 mg (65%) of thedesired product as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.10 (t,3H),2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m,1H), 3.05-3.20 (m, 1H), 3.48(d, J=7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm;³¹P (121.4 MHz, CD₃OD) δ 14.18 ppm; MS (m/z) 394 [M−H]⁻, 396 [M+H]⁺.

EXAMPLE 275 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{2-Ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonicacid diisopropyl ester

To a solution of bromomethylphosphonate diisopropyl ester (680 mg, 2.62mmol) and6-(3-hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(688 mg, 1.75 mmol) in DMF (3 mL) was added lithium t-butoxide (1.0M inTHF; 2.6 mL). The reaction was heated at 70° C. for 2 hours. Aftercooling to ambient temperature, more bromomethylphosphonate diisopropylester (680 mg, 2.62 mmol) and lithium t-butoxide (1.0M in THF; 2.6 mL)were added. The reaction mixture was heated at 70° C. for a furtherhour, cooled, poured into a solution of lithium chloride (5% aqueous)and extracted with ethyl acetate. The organic extract was dried and theproduct was purified by chromatography on silica gel, eluting withhexane-ethyl acetate to provide 347 mg (35%) of the product as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.09 (t, 3H,J=7.5 Hz), 1.20-1.26 (m, 2H), 1.31 (t, 12H, J=6 Hz), 2.18 (s, 3H), 2.29(q, 2H, J=7.5 Hz), 3.5 (m, 2H), 3.59 (d, 2H, J=8.7 Hz), 3.78 (s, 3H),3.98 (s, 2H), 4.28-4.35 (m, 2H), 4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t,1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 20.26 ppm; MS (m/z) 593.3[M+Na]⁺.

[2-Ethyl-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyloxymethyl]-phosphonicacid

To a solution of{2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonicacid diisopropyl ester (347 mg, 0.61 mmol) in acetonitrile (5 mL) wasadded 2,6-lutidine (0.71 mL, 6.1 mmol) and bromotrimethylsilane (0.786mL, 6.1 mmol). The mixture was stirred at room temperature for 3 hours,quenched with methanol (5 mL), concentrated, and partitioned betweenethyl acetate and 1N HCl (aqueous). The organic layer was concentratedto give the free phosphonic acid as a colorless oil (205 mg, 70%). Thismaterial (20 mg) was dissolved in a solution of trifluoroacetic acid(0.3 mL) and dichloromethane (2.7 mL) and stirred for 30 minutes atambient temperature. After concentration, the residue was purified by RPHPLC using a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile,0.1% TFA to provide the product, after lyophilization, as a white solid(10 mg). ¹H NMR (300 MHz, CDCl₃) δ 1.007 (t, 3H, J=7.5 Hz), 2.13 (s,3H), 2.32 (q, 2H, J=7.5 Hz), 3.41 (d, 2H, J=6.3 Hz), 3.56 (d, 2H, J=9Hz), 3.75 (s, 3H), 3.95 (s, 2H), 5.16 (s, 2H), 5.43 (t, 1H, J=6.3 Hz)ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.8 ppm; MS (m/z) 385.2 [M−H]⁺, 387.1[M+H]⁺.

EXAMPLE 276 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-Allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester

To a solution of 6-allyloxy-4-hydroxy-3-methyl-phthalic acid dimethylester (8.06 g, 28.8 mmol) [synthesized according to: J. W. Patterson,Tetrahedron, 1993, 49, 4789-4798] and pyridine (11.4 g, 144.0 mmol) indichloromethane (DCM) (20 mL) at 0° C. was added triflic anhydride(12.19 g, 43.2 mmol). The reaction was stirred at 0° C. for 2 hoursafter which additional triflic anhydride (3 mL) was added. Stirring at0° C. was continued for an additional hour. The reaction mixture waspoured into a mixture of DCM and HCl (1N). The layers were separated andthe aqueous layer was extracted with DCM. The combined organic layerswere dried over sodium sulfate. Filtration and evaporation of solventsin vacuo yielded a crude product, which was purified by silica gelchromatography to provide 8.39 g of the product as an oil. ¹H NMR (300MHz, CDCl₃): δ=2.32 (s, 3H), 3.89 (s, 6H), 4.60 (m, 2H), 5.33 (d, J=9.3Hz, 1H), 5.41 (d, J=18.6 Hz, 1H), 5.95 (m, 1H), 6.95 (s, 1H) ppm; ¹⁹FNMR (282 MHz, CDCl₃): δ=−74 ppm.

6-Hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester

To a solution of6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester (8.39 g, 20.3 mmol) in toluene (20 mL) was addedtetrakistriphenylphosphine palladium (0.47 g, 0.40 mmol) anddiethylamine (2.97 g, 40.86 mmol) at room temperature under anatmosphere of nitrogen. Stirring at room temperature was continued untilall starting material was consumed. The crude reaction mixture waspartitioned between diethyl ether and HCl (0.1 N). The organic layer waswashed with brine and dried over sodium sulfate. Filtration andevaporation of solvents in vacuo yielded a crude material, which waspurified by silica gel chromatography to provide 4.16 g (55%) of thedesired product as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ=2.20(s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; ¹⁹F NMR (282 MHz,CDCl₃): δ=−74 ppm.

6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester

To a solution of6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester (2.17 g, 5.85 mmol) in N-methylpyrolidinone (15 mL) was addedlithium chloride (743 mg, 17.5 mmol) and triphenylarsine (179 mg, 0.585mmol). Tributylvinyltin (2.04 g, 6.43 mmol) was added followed bytris(tribenzylideneacetone)dipalladium(0)-chloroform adduct (90 mg,0.087 mmol). The reaction was placed under an atmosphere of nitrogen andheated at 60° C. for 18 hours. The reaction was cooled to roomtemperature and poured onto a mixture of ice (20 g), EtOAc (40 mL), andpotassium fluoride (1 g). Stirring was continued for 1 hour. The aqueouslayer was extracted with EtOAc and the organic extracts filtered throughCelite. The combined organic layers were washed with water and driedover sodium sulfate. Filtration and evaporation of solvents in vacuoyielded a crude material, which was purified by silica gelchromatography to provide 1.27 g (87%) of the product as an off-whitesolid. ¹H NMR (300 MHz, CDCl₃): δ=2.16 (s, 3H), 3.91 (s, 3H), 3.92 (s,3H), 5.46 (dd, J=11.1, 1.2 Hz, 1H), 5.72 (dd, J=17.1, 0.9 Hz, 1H), 6.86(dd, J=17.1, 11.1 Hz, 1H), 7.14 (s, 1H), 10.79 (s, 1H) ppm.

4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester

6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester (1.27 g, 5.11mmol) was dissolved in benzene (10 mL) and EtOAc (10 mL).Tristriphenylphosphine rhodium chloride (150 mg) was added and thereaction was placed under an atmosphere of hydrogen. Stirring at roomtemperature was continued. After 14 hours, the solvents were removed invacuo and the crude material was purified by silica gel chromatographyto provide 1.14 g (88%) of the desired product as an off-white solid. ¹HNMR (300 MHz, CDCl₃): δ=1.19 (t, J=7.8 Hz, 3H), 2.10 (s, 3H), 2.60 (q,J=7.8 Hz, 2H), 3.89 (s, 6H), 6.87 (s, 1H), 10.79 (s, 1H) ppm.

1 6-Allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester

4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester (1.01 g, 4.02mmol) was dissolved in DMF (5 mL). Potassium carbonate (3.33 g, 24.14mmol) was added, followed by allylbromide (2.92 g, 24.14 mmol). Thesuspension was heated at 60° C. After 14 hours, the reaction was cooledto room temperature and filtered. The solvents were removed in vacuo andthe crude material was purified by silica gel chromatography to provide0.976 g (83%) of the desired product as a colorless oil. ¹H NMR (300MHz, CDCl₃): δ=1.16 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 2.62 (q, J=7.2 Hz,2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.57 (m, 2H), 5.26 (dd, J=9.3, 1.5 Hz,1H), 5.41 (dd, J=13.5, 1.5 Hz, 1H), 5.98 (m, 1H), 6.82 (s, 1H) ppm.

4-Allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester

6-Allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester (1.25 g, 4.28mmol) was heated at 210° C. under an atmosphere of nitrogen. After 14hours, the reaction was cooled to room temperature. The crude materialwas purified by silica gel chromatography to provide 0.971 g (77%) ofthe desired product as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ=1.14(t, J=7.8 Hz, 3H), 2.17 (s, 3H), 2.68 (q, J=7.8 Hz, 2H), 3.49 (m, 2H),3.86 (s, 3H), 3.89 (s, 3H), 4.89-5.01 (m, 2H), 5.93 (m, 1H), 11.22 (s,1H) ppm.

5 6-Allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one

4-Allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester (0.971g, 3.32 mmol) was dissolved in MeOH (8 mL) at room temperature. Asolution of sodium hydroxide (0.798 g, 19.95 mmol) in water (10 mL) wasadded and the suspension was heated at 55° C. After 16 hours, thereaction was cooled to room temperature and washed with diethyl ether.The aqueous layer was acidified (1N HCl) and the suspension wasextracted with EtOAc. The combined organic layers were dried over sodiumsulfate. Filtration and evaporation of solvents in vacuo yielded thedesired bis acid as a white solid (0.846 g, 98%, M⁺=263). The bis acidwas dissolved in acetic acid (6 mL) and HCl (conc., 1.5 mL). Thereaction was heated at 80° C. Zn dust (0.635 g, 9.72 mmol, each) wasadded in portions every hour for 7 hours. Stirring at 80° C. wascontinued for additional 10 hours. The reaction was cooled to roomtemperature, and water was added. The resultant suspension was extractedwith EtOAc. The combined organic extracts were washed with sodiumbicarbonate solution and dried over sodium sulfate. Filtration andevaporation of solvents in vacuo yielded the crude product, which waspurified by silica gel chromatography to provide 0.375 g (50%) of theproduct as a white solid. ¹H NMR (300 MHz, CDCl₃): δ=1.14 (t, J=7.5 Hz,3H), 2.18 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 3.49 (m, 2H), 4.95 (d, J=17.1Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.23 (s, 2H), 5.98 (m, 1H), 7.66 (s,1H) ppm.

56-Allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)₃H-isobenzofuran-1-one

To a solution of6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one (199 mg, 0.857mmol), PPh₃ (337 mg, 1.286 mmol), and 2-trimethylsilylethanol in THF (3mL) at 0° C. was added diisopropyl azodicarboxylate (259 mg, 1.286mmol). The resulting yellow solution was allowed to warm to roomtemperature and stirred for one hour. The solvent was removed in vacuoand the crude material was dissolved in diethyl ether (3 mL). Hexanes(1.5 mL) were added. Triphenylphosphine oxide was removed by filtrationand the filtrate was concentrated and purified by silica gelchromatography to provide the desired product (261 mg, 92%) as a clearoil. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H),1.25 (m, 2H), 2.20 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 3.54 (m, 2H), 4.28(m, 2H), 4.95 (d, J=17.1 Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.15 (s, 2H),5.95 (m, 1H) ppm.

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde

A solution of6-allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(261 mg, 0.788 mmol) in MeOH (5 mL), CH₂Cl₂ (5 mL) and pyridine (50 μL)was cooled to −78° C. using a dry ice/acetone bath according to theprocedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. Astream of ozone was bubbled through the reaction via a gas dispersiontube until the reaction became blue in color (15 minutes). The ozoneline was replaced with a stream of nitrogen and bubbling continued foranother 15 minutes, by which time the blue color had disappeared. Tothis solution, at −78° C., was added thiourea (59.9 mg, 0.788 mmol) inone portion, and the cooling bath was removed. The reaction was allowedto warm to room temperature and stirred for 15 hours. The reactionmixture was filtered and then partitioned between CH₂Cl₂ and water. Theaqueous layer was extracted with CH₂Cl₂ one more time and the organicextracts were combined, washed with aqueous 1N HCl, saturated NaHCO₃ andbrine and dried over sodium sulfate. Filtration and evaporation ofsolvents in vacuo yielded the crude product, which was purified bysilica gel chromatography to afford 181 mg (69%) of the product as awhite solid. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.11 (t, J=7.5 Hz,3H), 1.19 (m, 2H), 2.21 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.90 (s, 2H),4.36 (m, 2H), 5.18 (s, 2H), 9.71 (s, 1H) ppm.

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-propionaldehyde(72.9 mg, 0.23 mmol) in toluene (3 mL) were heated at 100° C. After 15hours, a second portion of 2-(triphenyl-phosphanylidene)-propionaldehyde(33 mg, 0.111 mmol) was added and the reaction mixture was heated foradditional 9 hours. The toluene was removed in vacuo, and the residuewas purified by silica gel chromatography to provide 77.6 mg (77%) ofthe desired product as a pale yellow oil. ¹H NMR (300 MHz, CDCl₃):δ=0.03 (s, 9H), 1.15 (t, J=7.5 Hz, 3H), 1.21 (m, 2H), 1.93 (s, 3H), 2.21(s, 3H), 2.71 (q, J=7.5 Hz, 2H), 3.82 (d, J=6.9 Hz, 2H), 4.34 (m, 2H),5.18 (s, 2H), 6.38 (m, 1H), 9.35 (s, 1H) ppm.

5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)₄-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(77.6 mg, 0.207 mmol) was dissolved in MeOH (4 mL). A solution of CeCl₃(51.1 mg, 0.207 mmol) in MeOH/water (9/1, 0.66 mL) was added and thesolution was cooled to 0° C. A solution of lithium borohydride in THF(2M, 0.105 mL) was added dropwise. After 15 minutes, the reaction wasquenched with 1N HCl (0.5 mL). The MeOH was removed in vacuo and thecrude material was partitioned between DCM and water. The aqueous layerwas extracted with DCM and the combined organic layers were washed withsodium bicarbonate solution and dried over sodium sulfate. Filtrationand evaporation of solvents yielded a crude oil, which was purified bysilica gel chromatography to provide 57.2 mg (73%) of the desiredproduct. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz,3H), 1.26 (m, 2H), 1.86 (s, 3H), 2.19 (s, 3H), 2.72 (q, J=7.8 Hz, 2H),3.52 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 4.34 (m, 2H), 5.14 (s, 2H), 5.32(m, 1H) ppm.

6-(4-Bromo-3-methyl-but-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(57.2 mg, 0.152 mmol) was dissolved in DCM (3.5 mL). Polymer-boundtriphenylphosphine (3 mmol/g, 152.1 mg) was added and the mixture wasmechanically stirred at room temperature. Carbon tetrabromide (151.3 mg,0.456 mmol) was added and the solution was stirred at room temperature.After 2 hours, the reaction was filtered and the solvent was removed invacuo. The crude material was purified by silica gel chromatography toprovide 58.0 mg (87%) of the desired product. ¹H NMR (300 MHz, CDCl₃):δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.25 (m, 2H), 1.95 (s, 3H), 2.20(s, 3H), 2.70 (q, J=7.8 Hz, 2H), 3.52 (d, J=6.3 Hz, 2H), 3.94 (s, 2H),4.28 (m, 2H), 5.14 (s, 2H), 5.50 (m, 1H) ppm.

{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy}1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid

A solution of4-[6′-ethyl-7′-methyl-3′-oxo-4′-(2″-trimethylsilanyl-ethoxy)-1′,3′-dihydro-isobenzofuran-5′-yl]-2-methyl-but-2-enylbromide (58 mg, 0.132. mmol) in trimethylphosphite (0.8 mL) was heatedat 110° C. After 2 hours the reaction was complete. The reaction wascooled to room temperature and the excess trimethylphosphite was removedin vacuo. The crude material was used in the next step without furtherpurification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8mL). Trimethylsilyl bromide (202.2 mg, 1.321 mmol) was added and thereaction was stirred at room temperature. After 15 minutes, lutidine(155.7 mg, 1.453 mmol) was added and stirring at room temperature wascontinued. After 2 hours, additional trimethylsilyl bromide (202.2 mg,1.321 mmol) was added and stirring at room temperature was continued.After 4 hours, the reaction was quenched with MeOH (2 mL). The solventswere evaporated in vacuo, and the crude material was purified by RP-HPLC(eluent: water/MeCN). The product-containing fractions were combined andlyophilized to yield 2.3 mg (5.1%) of the free phosphonic acid. ¹H NMR(300 MHz, DMSO-d₆): δ=1.07 (t, J=7.5 Hz, 3H), 1.84 (s, 3H), 2.14 (s,3H), 2.64 (q, J=7.5 Hz, 2H), 3.34 (m, 4H), 5.06 (m, 1H), 5.25 (s, 2H)ppm; ³¹P NMR (121 MHz, DMSO-d₆): δ=22.19 ppm; MS=341 [M⁺+1].

EXAMPLE 277 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-butyraldehyde(98.4 mg, 0.296 mmol) in toluene (3 mL) were heated at 100° C. After 15hours, a second portion of 2-(triphenyl-phosphanylidene)-butyraldehyde(98.4 mg, 0.296 mmol) was added and the reaction mixture was heated foradditional 33 hours. After concentration, the residue was purified bysilica gel chromatography to provide 50.3 mg (48%) of the desiredproduct as a pale yellow oil.

5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)₄-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(50.3 mg, 0.129 mmol) was dissolved in MeOH (3 mL). A solution of CeCl₃(31.9 mg, 0.129 mmol) in MeOH/water (9/1, 0.66 mL) was added and thesolution was cooled to 0° C. A solution of lithium borohydride in THF(2M, 0.065 mL) was added dropwise. After 10 minutes, the reaction wasquenched with 1N HCl (0.5 mL). The methanol was removed in vacuo and thecrude material was partitioned between DCM and water. The aqueous layerwas extracted with DCM and the combined organic layers were washed withsodium bicarbonate solution and were dried over sodium sulfate.Filtration and evaporation of solvents in vacuo yielded a crude oil,which was purified by silica gel chromatography to provide 35.4 mg (70%)of the desired product. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H),1.10-1.19 (m, 6H), 1.26 (m, 2H), 2.19 (s, 3H), 2.32 (q, J=7.5 Hz, 2H),2.72 (q, J=7.5 Hz, 2H), 3.54 (d, J=6.6 Hz, 2H), 4.05 (s, 2H), 4.26 (m,2H), 5.14 (s, 2H), 5.27 (m, 1H) ppm.

6-(3-Bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(35.4 mg, 0.090 mmol) was dissolved in DCM (3.0 mL). Polymer-boundtriphenylphosphine (3 mmol/g, 90.7 mg) was added, and the mixture wasmechanically stirred at room temperature. Carbon tetrabromide (90.2 mg,0.272 mmol) was added and the solution was stirred at room temperature.After 2 hours, the reaction was filtered and the solvent was removed invacuo. The crude material was purified by silica gel chromatography toprovide 32.0 mg (78%) of the desired product. The material was used inthe next step without further characterization.

[2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonicacid

A solution of6-(3-bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(32 mg, 0.070 mmol) in trimethylphosphite (0.8 mL) was heated at 110° C.After 2 hours, the reaction was complete. The reaction was cooled toroom temperature and the excess trimethylphosphite was removed in vacuo.The crude material was used in the next step without furtherpurification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8mL). Trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and thereaction was stirred at room temperature. After 2 hours, a second batchof trimethysilyl bromide (108.0 mg, 0.706 mmol) was added. After 3hours, the reaction was quenched with MeOH (2 mL). The solvents wereevaporated in vacuo and the crude material was purified by RP-HPLC(eluent: water/MeCN). The product-containing fractions were combined andlyophilized to yield 15.7 mg (63%) of the product. ¹H NMR (300 MHz,DMSO-d₆): δ=0.98-1.09 (m, 6H), 2.10 (s, 3H), 2.30 (m, 2H), 2.64 (q,J=7.5 Hz, 2H), 3.38 (m, 4H), 5.03 (m, 1H), 5.25 (s, 2H) ppm; 31P NMR(121 MHz, DMSO-d₆): δ=22.26 ppm; MS=355 [M⁺+1].

EXAMPLE 278 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethylester oxalatesalt (15.6 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). Acetic acid(15.7 mg, 0.263 mmol) was added, followed by sodiumtriacetoxyborohydride (22.3 mg, 0.105 mmol). After 4 hours, the crudereaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide27.7 mg (97%) of the desired product after lyophilization. ¹H NMR (300MHz, CDCl₃): δ=0.04 (s, 9H), 1.14 (t, J=7.5 Hz, 3H), 1.26 (m, 2H), 1.30(t, J=7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q,J=7.5 Hz, 2H), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m, 4H), 4.28 (m, 2H),5.15 (s, 2H), 5.51 (m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.39 ppm;MS=540 [M⁺+1].

{2-[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphonicacid

(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (27.7 mg, 0.051 mmol) was dissolved in DMF (0.5 mL)and DCM (0.5 mL). Trimethylsilyl bromide (78.3 mg, 0.512 mmol) was addedand the reaction was stirred at room temperature. After 20 hours, thereaction was quenched with MeOH (0.3 mL). The solvents were evaporatedin vacuo and the crude material was purified by RP-HPLC (eluent:water/MeCN). The product-containing fractions were combined andlyophilized to yield 14.2 mg (57%) of the free phosphonic acid [MS: 484M⁺+1].

The material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added andstirring at room temperature was continued. After 20 minutes, thesolvents were removed in vacuo and the crude material was purified byRP-HPLC (eluent: water/MeCN*0.1% TFA). The product-containing fractionswere combined and lyophilized to yield 7.6 mg (52%) of the product asthe TFA salt. ¹H NMR (300 MHz, DMSO-d₆): δ=1.07 (t, J=7.5 Hz, 3H), 1.84(s, 3H), 1.90 (m, 2H), 2.11 (s, 3H), 2.63 (q, J=7.5 Hz, 2H), 2.99 (m,2H), 3.43 (d, J=6.3 Hz, 2H), 3.51 (s, 2H), 5.26 (s, 2H), 5.45 (m, 1H)ppm; ³¹P NMR (121 MHz, DMSO-d₆): δ=20.02 ppm; MS=384 [M⁺+1].

(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethylester oxalatesalt (20.4 mg, 0.075 mmol) were dissolved in DMF (0.8 mL). Acetic acid(20.5 mg, 0.342 mmol) was added, followed by sodiumtriacetoxyborohydride (27.6 mg, 0.137 mmol). After 8 hours, the crudereaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide24.9 mg (65%) of the desired product after lyophilization. ¹H NMR (300MHz, CDCl₃): δ=0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J=7.5 Hz, 6H),2.19 (s, 3H), 2.23 (m, 2H), 2.35 (q, J=7.8 Hz, 2H), 2.70 (q, J=7.2 Hz,2H), 3.25 (m, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s,2H), 5.47 (m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.71 ppm; MS=554[M⁺+1].

{2-[2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enylamino]-ethyl}-phosphonicacid

(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (24.9 mg, 0.045 mmol) was dissolved in DMF (0.5 mL)and DCM (0.5 mL). Trimethylsilyl bromide (68.7 mg, 0.449 mmol) was addedand the reaction was stirred at room temperature. After 20 hours, thereaction was quenched with MeOH (0.15 mL). The solvents were evaporatedin vacuo and the crude material was purified by RP-HPLC (eluent:water/MeCN). The product-containing fractions were combined andlyophilized to yield 8.0 mg of the free phosphonic acid [MS: 498 M⁺+1].

This material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added,and stirring at room temperature was continued. After 20 minutes, thesolvents were removed in vacuo and the crude material was purified byRP-HPLC (eluent: water/MeCN*0.1% TFA). The product-containing fractionswere combined and lyophilized to yield 4.4 mg (54%) of the product asthe TFA salt. ¹H NMR (300 MHz, DMSO-d₆): δ=1.05 (m, 6H), 1.60 (m, 2H),2.10 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 2.63 (q, J=6.9 Hz, 2H), 2.93 (m,2H), 3.45 (m, 4H), 5.24 (s, 2H), 5.36 (m, 1H) ppm.; ³¹P NMR (121 MHz,DMSO-d₆): δ=16.93 ppm; MS=398 [M⁺+1].

EXAMPLE 279 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-({4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydroisobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester

4-[6′-ethyl-7′-methyl-3′-oxo-4′-(2″-trimethylsilanyl-ethoxy)-1′,3′-dihydro-isobenzofuran-5′-yl]-2-methyl-but-2-en-phosphonicacid (44.8 mg, 0.101 mmol), dicyclohexylcarbodiimide (52.6 mg, 0.254mmol), and phenol (95.8 mg, 1.018 mmol) were dissolved in pyridine (0.3mL) and heated at 70° C. for 4 hours. The reaction mixture was cooled toroom temperature and the pyridine was removed in vacuo. The crudematerial was partitioned between DCM and HCl (0.1N). The aqueous layerwas extracted with DCM and the combined organic layers were dried oversodium sulfate. Filtration and evaporation of solvents in vacuo yieldeda crude material, which was used in the next step without furtherpurification.

The crude material was dissolved in MeCN (0.8 mL) and water (0.3 mL).Aqueous sodium hydroxide solution (2N, 0.8 mL) was added in portions(0.2 mL). After all starting material was consumed, the organic solventwas removed in vacuo and the crude material was partitioned betweenchloroform and aqueous HCl (1N). The aqueous layer was extracted withchloroform. The combined organic layers were dried over sodium sulfate.Filtration and evaporation of solvents yielded the crude product as amixture of mono phenyl ester and the symmetrical anhydride.

The crude material of the previous step and ethyl (L)-alaninehydrochloride salt (78.1 mg, 0.509 mmol) were dissolved in DMF (0.4 mL).DMAP (1.2 mg, catalytic) was added, followed by diisopropylethylamine(131.3 mg, 1.018 mmol). Stirring at room temperature was continued.After 20 minutes, complete conversion of the anhydride was observed.After 2 hours, PyBOP (101 mg, 0.202 mmol) was added and stirring at roomtemperature was continued. The reaction was filtered and the crudereaction solution was purified by RP-HPLC (eluent: water/MeCN). Theproduct-containing fractions were combined and lyophilized to yield theproduct (15.7 mg, 25% over three steps) as a white powder. ¹H NMR (300MHz, CDCl₃): δ=0.03 (s, 9H), 1.13-1.28 (m, 8H), 2.03 (s, 3H), 2.19 (s,3H), 2.62-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 4.03 (m,3H), 4.30 (m, 2H), 5.14 (s, 2H), 5.31 (m, 1H), 7.11-7.17 (m, 3H),7.25-7.30 (m, 2H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.04, 27.73 ppm;MS=615 [M⁺+1].

2-{[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

2-({4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester (7.5 mg, 0.012 mmol) was dissolved in TFA/DCM (10%, 0.3mL) at −20° C. The reaction mixture was warmed to 0° C. and stirred atthis temperature for 45 minutes. Pyridine (0.09 mL) was added thesolvents were removed in vacuo. The crude material was purified byRP-HPLC (eluent: water/MeCN). The product-containing fractions werecombined and lyophilized, yielding a white powder (5.5 mg, 87%). ¹H NMR(300 MHz, CDCl₃): δ=1.12-1.29 (m, 6H), 2.03 (s, 3H), 2.17 (s, 3H),2.65-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 4.03 (m, 3H),5.22 (s, 2H), 5.36 (m, 1H), 7.11-7.16 (m, 3H), 7.24-7.30 (m, 2H), 7.72(m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.11, 27.57 ppm; MS=515[M⁺+1].

EXAMPLE 280 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoicacid

A mixture of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (1.5 g, 3.45 mmol) and sodium hydroxide (552 mg) in amixture of methanol (20 mL) and water (7 mL) was stirred at roomtemperature for one hour. The solution was acidified with 1N HCl. Theprecipitate was collected by suction filtration and washed with water togive the desired product (1.2 g, 83%). ¹H NMR (300 MHz, CDCl₃) δ 0.02(s, 9H), 1.15-1.22 (m, 2H), 1.76 (s, 3H), 2.13 (s, 3H), 2.12-2.28 (m,2H), 2.35-2.41 (m, 2H), 3.37 (d, 2H, J=7 Hz), 3.71 (s, 3H), 4.22-4.28(m, 2H), 5.07 (s, 2H), 5.13-5.17 (m, 1H) ppm; MS (m/z) 419.3 [M−H]⁻,443.2 [M+Na]⁺.

({6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoylamino}-methyl)-phosphonicacid diethyl ester

To a solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate(17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. Afterstirring at 0° C. for 2 hours, diethyl (aminomethyl) phosphonate oxalate(62 mg, 0.26 mmol) was added and stirring was continued at roomtemperature for 20 minutes. After removal of solvent, the residue waspurified by preparative reverse-phase HPLC to afford 54.8 mg (81%) ofthe desired product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.15-1.22(m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41(d, 2H, J=7 Hz), 3.65 (dd, 2H, J=6, 12 Hz), 3.77 (s, 3H), 3.77-4.16 (m,4H), 4.26-4.32 (m,2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 5.86 (bs, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 23.01 ppm; MS (m/z) 568 [M−H]⁻, 592[M+Na]⁺.

{[6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoylamino]methyl}-phosphonicacid

To a solution of({6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonicacid diethyl ester (40 mg, 0.07 mmol) in acetonitrile (1 mL) was addedTMSBr (91 μL, 0.7 mmol) followed by 2,6-lutidine (81.5 μL, 0.7 mmol).The reaction was allowed to proceed overnight when it was completed asjudged by LCMS. The reaction mixture was quenched with MeOH andconcentrated to dryness. The residue was purified by preparativereverse-phase HPLC to afford 2.6 mg (9%) of desired product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.67 (s, 3H), 2.17 (m, 5H), 2.30-2.46(m, 2H), 2.80-2.86 (m, 2H), 3.55 (m, 2H), 3.82 (s, 3H), 5.26 (s, 3H)ppm; ³¹P (121.4 MHz, CD₃OD) δ 10.27 ppm; MS (m/z) 412 [M−H]⁻, 414[M+H]⁺.

EXAMPLE 281 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate(17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. Afterstirring at 0° C. for 2 hours, diethyl (aminoethyl) phosphonate oxalate(62 mg, 0.26 mmol) was added and stirred at room temperature wascontinued for one hour. After removal of solvent, the residue waspurified by preparative reverse-phase HPLC to afford 37 mg (54%) of thedesired product as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s,9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 1.85-1.93 (m,2H),2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.48-3.54 (m, 2H),3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m,2H), 5.12 (s, 2H),5.17-5.19 (m, 1H), 6.30 (bs, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.91ppm; MS (m/z) 584 [M+H]⁺.

{2-[6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoylamino]-ethyl}-phosphonicacid

To a solution of(2-{6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonicacid diethyl ester (36.6 mg, 0.063 mmol) in acetonitrile (1 mL) wasadded TMSBr (81 μL, 0.63 mmol) followed by 2,6-lutidine (73 μL, 0.63mmol). The reaction was allowed to proceed overnight, when it wascompleted as judged by LCMS. The reaction mixture was quenched with MeOHand concentrated to dryness. The residue was purified by preparativereverse-phase HPLC to afford 5.8 mg (29%) of desired product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.80 (s, 3H), 2.14 (m, 5H), 2.25 (m,4H), 3.35 (m, 2H), 3.38-3.38 (m, 2H), 3.75 (s, 3H), 5.23 (s, 3H) ppm;³¹P (121.4 MHz, CD₃OD) δ 26.03 ppm; MS (m/z) 426 [M−H]⁻, 428 [M+H]⁺.

EXAMPLE 282 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid diphenyl ester

To a solution of[{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid (260 mg, 0.59 mmol) in DMF (6 mL) and phenol (555 mg, 5.9 mmol) wasadded dicyclohexyl carbodiimide (1.21 g, 5.9 mmol) and DMAP (36 mg,0.295 mmol). The reaction mixture was heated to 140° C. for 30 minutes.After cooling to room temperature, the mixture was partitioned betweenEtOAc/Hexane (1:1) and 5% aqueous LiCl solution. The organic layer waswashed with 5% aqueous LiCl solution repeatedly, then dried over Na₂SO₄.After removal of solvent, the residue was purified by silica gelchromatography to provide 75 mg (21%) of the desired product. MS (m/z)617 [M+Na]⁺.

{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester

To a solution of{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid diphenyl ester (75 mg, 0.126 mmol) in THF (5 mL) was added 1N NaOH(0.1 mL) solution. The mixture was allowed to stir at room temperaturefor 16 hours. EtOAc was added and the resulting mixture was washed with1H HCl. The organic layer was concentrated to dryness and the residuewas purified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 24.8 mg (38%) of the desiredproduct. MS (m/z) 517 [M−H]⁻, 541 [M+Na]⁺.

2-({4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester

To a solution of{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester (25 mg, 0.048 mmol) and ethyl (S)-(−)-lactate (34mg, 0.288 mmol) in pyridine (1 mL) was added PyBOP (125 mg, 0.24 mmol).The solution was stirred at room temperature for 16 hours andconcentrated. The residue was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24 mg(83%) of the desired product. MS (m/z) 641 [M+Na]⁺.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

To a solution of2-({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester (24 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.5mL) and the mixture was stirred at room temperature for 10 minutes. Thereaction mixture was dried under reduced pressure and the residue waspurified by RP-HPLC to provide 18 mg (90%) of the desired product as aclear oil. ¹H NMR (300 MHz, CDCl₃) δ 1.18-1.34 (m, 3H), 1.36-1.48(dd,3H), 2.02 (m, 3H), 2.17 (s, 3H), 2.78-2.98 (dd, 2H), 3.45 (m, 2H),3.79 (s, 3H), 4.05-4.25 (m, 2H), 4.97 (m, 1H), 5.21 (s, 2H), 5.48 (t,J=7.2 Hz, 1H), 7.05-7.18 (m, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 24.59,26.13 ppm; MS (m/z) 517 [M−H]⁻, 519 [M+H]⁺.

EXAMPLE 283 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid

To a solution of2-{[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester (10 mg, 0.019 mmol) in THF (3 mL) was added 1N NaOH(232 μL), and the mixture was stirred at room temperature for 1 hour.The reaction mixture was dried under reduced pressure and the residuewas purified by RP-HPLC to provide 6 mg (77%) of the desired product asa clear oil. ¹H NMR (300 MHz, CD₃OD) δ 1.41 (d, J=7 Hz, 3H), 1.97 (s,3H), 2.16 (s, 3H), 2.59 (d, J=22 Hz, 2H), 3.45 (m, 2H), 3.79 (s, 3H),4.83 (m, 1H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz,CD₃OD) δ 27.02 ppm; MS (m/z) 413 [M−H]⁻, 415 [M+H]⁺.

EXAMPLE 284 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester (1 g, ˜1.9 mmol) was combined with pyBOP (2 g, 4mmol) and DMAP (120 mg, 0.96 mmol). A solution of L-alanine ethyl esterhydrochloride salt (2.9 g, 19 mmol) and diisopropylethylamine (6.7 mL,38 mmol) in pyridine (5 mL) was added to the monoacid mixture and thereaction was stirred at room temperature for 12 hours. The reactionmixture was then concentrated and purified twice by columnchromatography (1% MeOH/CH₂Cl₂ 3% MeOH/CH₂Cl₂). The resulting oil wasdissolved in a vigorously-stirred solution of 10% TFA/CH₂Cl₂ (30 mL) at−40° C. The reaction was gradually warmed to 0° C. After about 3 hours,the reaction was complete. Pyridine (4.5 mL) was added, and the reactionmixture was concentrated. The product was purified by preparative TLC(5% MeOH/CH₂Cl₂) and concentrated to give 210 mg (21%) of the desiredproduct as a light yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.83-7.70 (m,1H), 7.30-7.20 (m, 2H), 7.18-7.03 (m, 3H), 5.60-5.35 (m, 1H), 5.21 (s,2H), 4.17-3.95 (m, 3H), 3.79 (s, 3H), 3.60-3.40 (m, 3H), 2.80-2.60 (m,2H), 2.17 (m, 3H), 2.01 (m, 3H), 1.30-1.10 (m, 6H) ppm; ³¹P NMR (121MHz, CDCl₃) δ 28.0, 27.5 ppm; MS (m/z) 516 [M−H]⁻.

EXAMPLE 285 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-(Dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoicacid methyl ester

To a solution of trimethylphosphonoacetate (63 μL, 0.39 mmol) in THF (1mL) was added NaN(TMS)₂ (0.39 mmol, 0.39 mL) at ambient temperature.After 30 minutes, a solution of6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(69 mg, 0.156 mmol) in THF (1 mL) was added. The reaction mixture wasstirred for 2 hours, when a precipitate was observed. The reactionmixture was worked up by addition of a saturated aqueous solution ofammonium chloride and extraction of the product with EtOAc. The organicextract was dried and the product was purified using silica gelchromatography with 0-100% EtOAc-Hexanes to provide 40 mg of the desiredproduct as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s, 9H),1.20-1.26 (m, 2H), 1.79 (s, 3H), 2.17 (s, 3H), 2.42-2.72 (m, 2H), 3.19(ddd, 1H, J=4, 12, 23 Hz), 3.39 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.75 (s,3H), 3.77-3.84 (m, 6H), 4.27-4.34 (m, 2H), 5.12 (s, 2H), 5.24 (t, 1H,J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 25.1 ppm; MS (m/z) 565.2 [M+Na]⁺.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-2-phosphono-hex-4-enoicacid methyl ester

To a solution of2-(dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL) was addedtrimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16mL) was added to the reaction at ambient temperature. The reaction wasallowed to proceed for 16 hours before it was concentrated to dryness.The residue was resuspended in a solution of DMF: H₂O (8:2, 1 mL) andpurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 18 mg of the product as a whitepowder. ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49(m, 1H), 2.63 (dt, 1H, J=6, 17 Hz), 3.07 (ddd, 1H, J=4,12,23 Hz),3.38(3, 2H, J=7 Hz), 3.52 (s, 3H), 3.77 (s, 3H), 5.25 (s, 2H), 5.28 (t,1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 19.5 ppm; MS (m/z) 415.2[M+H]⁺, 437.2 [M+Na]⁺.

EXAMPLE 286 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acidmethyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added asolution of 1N NaN(TMS)₂ in THF (0.88 mL, 0.88 mmol). The solution wasstirred at room temperature for 30 minutes, whereupon a solution of6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture wasstirred overnight when a precipitate was observed. The reaction mixturewas worked up by addition of a saturated aqueous solution of ammoniumchloride and extraction of the product with EtOAc. The organic extractwas dried and the product was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg(48%) of the product as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.05(s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m,2H), 3.3 (ddd, 1H, J=4, 12,23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H),3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm;MS (m/z) 701.2 [M+Na]⁺.

2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-hydroxyoxy)-1,3-dihydro-isobenzofuran-5-yl]4-methyl-hex-4-enoicacid methyl ester

[2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (70 mg) was dissolved in a solution of 10%trifluoroacetic acid in dichloromethane (5 mL). After 10 minutes, themixture was concentrated and the product was purified by RP HPLC using aC18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA toprovide 45 mg (75%) of the product as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H),3.38 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.77 (s, 3H), 4.33-4.43 (m, 4H),5.21 (s, 2H), 5.33 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 25.8ppm; MS (m/z) 601.2 [M+Na]⁺.

EXAMPLE 287 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-[hydroxy-(2,2,2-trifluoro-ethoxy)-phosphoryl]4-methyl-hex4-enoic acid

To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acidmethyl ester (186 μL, 0.88 mmol) in anhydrous THF (0.5 mL) was added asolution of 1N NaOH (aqueous; 0.06 mL) and N-methylpyrrolidinone (0.2mL). After 6.5 hours, another aliquot of 1N NaOH (0.06 mL) was added andthe mixture was stirred overnight. After concentration, the residue wassuspended in DMF (<1 mL), neutralized with a few drops of TFA andpurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 5.6 mg (72%) of the product as awhite powder after lyophilization. ¹H NMR (300 MHz, CD₃OD) δ 1.83 (s,3H), 2.16 (s, 3H), 2.43-2.51 (m, 1H), 2.59-2.70 (m, 1H), 3.13 (ddd, 1H),3.40 (d, 2H), 3.76 (s, 3H), 4.36-4.47 (m, 2H), 5.25 (s, 2H), 5.34 (t,1H, J=7 Hz) ppm; MS (m/z) 505.2 [M+Na]⁺.

EXAMPLE 288 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

Phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

To a solution of6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(75 mg, 0.20 mmol) and DIEA (49 μL, 0.28 mmol) in dioxane (2 mL) wasadded 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg, 0.28 mmol)according the procedure of Shadid, B. et al., Tetrahedron, 1989, 45, 12,3889. After 10 minutes, another portion of2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA(35 μL, 0.20 mmol) were added. The reaction was allowed to proceed atroom temperature for an additional hour, after which it was quenched bythe addition of H₂O. The solution was stirred for another 10 minutes andconcentrated in vacuo to a small volume. The product was triturated withdiethyl ether and coevaporated from acetonitrile (4×10 mL) to providethe product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H),1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21-4.39(m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); ³¹P (121.4MHz, CDCl₃) δ 7.22; MS (m/z) 441 [M−H]⁻.

EXAMPLE 289 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

Phosphoric acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

A solution of phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester(27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at roomtemperature for 3 hours. To the reaction solution was added2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowedto stir for an additional 2 hours at room temperature. The reactionmixture was diluted by addition of H₂O and the solution was stirred for2 more hours when it was concentrated. The residue was dissolved in asolution of 10% TFA/CH₂Cl₂ and stirred at room temperature for 9 hours.The reaction mixture was dried under reduced pressure and the productwas purified by reverse-phase HPLC to provide the desired product as awhite solid. ¹H NMR (300 MHz, CD₃OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47(d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H),5.50-5.61 (m, 1H); ³¹P (121.4 MHz, CD₃OD) δ 0.50; MS (m/z) 357 [M−H]⁻.

EXAMPLE 290 Specific Embodiments of the Invention

Several compounds of the invention are presented below.

EXAMPLE 291 Preparation of Representative Compounds of the Invention

Additional representative compounds of the invention, and intermediatesthereof, can be prepared according to the methods presented below.

Synthesis of Phenacetaldehydes with Variants at R₁, R₂

The parent compound (R¹=OMe; R₂=Me) is accessible by semi-synthesis frommycophenolic acid as follows:

To a solution of mycophenolic acid (500 g, 1.56 mol) in MeOH (4 L) undernitrogen atmosphere was added sulfuric acid (10 mL) dropwise, and thesuspension was stirred at room temperature. After 2 hours, the reactionbecame homogeneous, and soon thereafter a precipitate was formed. Thereaction was allowed to stir at room temperature for 10 hours, at whichtime TLC indicated complete reaction. The reaction was cooled in an icebath to 10° C. and then filtered using a Buchner funnel. The filter cakewas washed with ice cold methanol (750 mL) followed by hexanes (750 mL)and then dried to give 497 g (95%) of the desired product as a solid: ¹HNMR (300 MHz, CDCl₃) δ, 1.81 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H),2.37-2.50 (m, 4H), 3.38 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H),5.13 (s, 2H), 5.22 (m, 1H), 7.17 (s, 1H).

To a solution (3.99 g, 11.9 mmol), PPh₃ (4.68 g, 17.9 mmol), anddiisopropyl azodicarboxylate (3.46 mL, 17.9 mmol) in THF (60 mL) at 0°C. was added a solution of 2-trimethylsilylethanol (2.05 mL, 14.3 mmol)in THF (20 mL). The resulting yellow solution was allowed to warm toroom temperature and stirred for 4 hours. The reaction was worked up byconcentrating the solution to dryness and addition of ether and hexanes.Triphenylphosphine oxide was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to provide 4.8 g(100%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.18-1.30(m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m,2H), 3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m,2H), 5.13 (s, 2H), 5.12-5.22 (m, 1H).

A solution (9.6 g, 22 mmol) in MeOH (90 mL), CH₂Cl₂ (90 mL) and pyridine(0.7 mL) was cooled to −70° C. using a dry ice/acetone bath. A stream ofozone was bubbled through the reaction via a gas dispersion tube untilthe reaction became blue in color (1.5 hours). The ozone line wasreplaced with a stream of nitrogen and bubbling continued for another 30minutes, by which time the blue color had disappeared. To this solutionat −70° C. was added thiourea (1.2 g, 15.4 mmol) in one portion, and thecooling bath was removed. The reaction was allowed to warm to roomtemperature and stirred for 15 hours. The reaction was worked up byfiltration to remove solid thiourea S-dioxide, and then partitionedbetween CH₂Cl₂ and water. The organic layer was removed. The aqueouslayer was washed with CH₂Cl₂ and the organic extracts were combined,washed with aqueous 1N HCl, saturated NaHCO₃ and brine, and dried invacuo. The residue was purified by silica gel chromatography to afford7.3 g (99%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 9H),1.05-1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz),4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J=1 Hz).

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The aldehyde is dissolved in an organic solvent such as methanol andsodium borohydride is added. At the end of the reaction, aqueous HClsolution is added and the solvent is removed in vacuo. Furtherpurification is achieved by chromatography.

The resulting alcohol is dissolved in an organic solvent such asdichloromethane (DCM). Pyridine and acetic anhydride are added andstirring at room temperature is continued. At the end of the reactionadditional DCM is added and the solution is washed with aqueous HClsolution, aqueous sodium bicarbonate solution, and dried over sodiumsulfate. Filtration and evaporation of the solvent in vacuo gives thecrude product. Further purification is achieved by chromatography.

The acetate is dissolved in DCM and bromine is added, according to aprocedure from J. Med. Chem., 1996, 39, 4181-4196. At the end of thereaction, additional DCM is added and the solution is washed withaqueous sodium thiosulfate solution and brine. The organic layer isdried over sodium sulfate. Filtration and evaporation of solvents yieldsthe crude material. Further purification is achieved by chromatography.

The product of the previous step, lithium chloride, triphenylarsine,tributylvinyltin, andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct are heated inan organic solvent such as N-methylpyrrolidinone at an elevatedtemperature of approximately 55° C., according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, the mixtureis cooled to room temperature and poured into a mixture of ice,potassium fluoride, water, and ethyl acetate. Stirring is continued forone hour. The suspension is filtered through Celite and extracted withethyl acetate. The combined organic extracts are dried over sodiumsulfate. The solvents are removed in vacuo and the crude material isfurther purified by chromatography.

The product of the previous step is dissolved in an organic solvent suchas DCM or THF. 1,1,1-tris(acyloxy)-1,1-dihydro-1,2benziodoxol-3-(1H)-one(Dess-Martin reagent) is added and the solution is stirred at roomtemperature, according to a procedure from J. Org. Chem., 1984, 48,4155-4156. At the end of the reaction diethyl ether is added, followedby aqueous sodium hydroxide solution. The layers are separated and theorganic layer is washed with aqueous sodium hydroxide solution, water,and dried over sodium sulfate. Filtration and evaporation of solventsyields the crude product. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such astoluene. P(isobutylNCH₂CH₂)₃N, palladium(II)acetate, sodiumtert.butoxide, and benzylamine are added and the mixture was heated at80° C., according to a procedure from J. Org. Chem., 2003, 68, 452-459.At the end of the reaction, the mixture is cooled to room temperatureand the solvents are removed in vacuo. The crude material is purified bychromatography. Any residual acetate is removed by brief treatment withmethanolic sodium methoxide.

The benzyl-protected aniline is dissolved in an organic solvent such asDMF. Palladium on carbon is added and the reaction mixture is placedunder an atmosphere of hydrogen. At the end of the reaction, the mixtureis filtered through Celite. The solvents are removed in vacuo. Furtherpurification is achieved by chromatography.

The resulting primary aniline is dissolved in an organic solvent such asTHF, acetonitrile, or DMF and is treated with formaldehyde and sodiumtriacetoxyborohydride as described in J. Org. Chem, 1996, 61, 3849-3862.The reaction is quenched with aqueous sodium bicarbonate and the productis extracted with an organic solvent such as ethyl acetate. The crudematerial is treated with di-t-butyl dicarbonate in an organic solventsuch as dimethylformamide and aqueous sodium hydroxide. The resultingcarbamate is purified by chromatography.

The primary alcohol product is dissolved in an organic solvent such asDCM or THF. 1,1,1-tris(acyloxy)-1,1-dihydro-1,2benziodoxol-3-(1H)-one(Dess-Martin reagent) is added and the solution is stirred at roomtemperature, according to a procedure from J. Org. Chem., 1984, 48,4155-4156. At the end of the reaction diethyl ether is added, followedby aqueous sodium hydroxide solution. The layers are separated and theorganic layer is washed with aqueous sodium hydroxide solution, water,and dried over sodium sulfate. Filtration and evaporation of solventsyields the crude product. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as DCM orTHF and is treated with the mixed anhydride of formic and pivalic acids,according to a procedure from Recl. Trav. Chem. Pay-Bas, 1982, 101, 460.At the end of the reaction, the solvent and all volatiles are removed invacuo and the crude product is further purified by chromatography.

The product is dissolved in an organic solvent such as DCM or THF.1,1,1-Tris(acyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martinreagent) is added and the solution was stirred at room temperature,according to a procedure from J. Org. Chem., 1984, 48, 4155-4156. At theend of the reaction diethyl ether is added, followed by aqueous sodiumhydroxide solution. The layers are separated and the organic layer iswashed with aqueous sodium hydroxide solution, water, and dried oversodium sulfate. Filtration and evaporation of solvents yields the crudeproduct. Further purification is achieved by chromatography.

The starting material is dissolved in an organic solvent such as DMF andreacted with N-chlorosuccinimide, according to a procedure from J. Med.Chem., 1996, 39, 4181-4196. After the starting material is consumed thereaction mixture is poured into water and the product is extracted withdiethyl ether. The combined organic layers are dried over sodiumsulfate. Filtration and evaporation of the solvent yields a crudereaction product.

The product of step one is dissolved in a mixture of organic solventssuch as methanol, DCM, and pyridine. The solution is cooled to −78° C.and ozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The starting material is dissolved in a mixture of organic solvents suchas methanol, DCM, and pyridine. The solution is cooled to −78° C. andozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution, and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The product of step one is dissolved in an organic solvent such asbenzene. Trifluoromethanesulfonyl chloride anddichlorotris(triphenylphosphine)rhuthenium are added and the solution isdegassed. The reaction mixture is heated at 120° C., according to aprocedure from J. Chem. Soc., Perkin Trans. 1, 1994, 1339-1346. At theend of the reaction the mixture is cooled to room temperature and thesolvent is removed in vacuo. Further product purification is achieved bychromatography.Synthesis of Olefins and Linkers to Phosphonates

The phenacetaldehyde (5.3 g, 15.8 mmol) in toluene (50 mL) was heated at100° C. with 2-(triphenyl-phosphanylidene)-propionaldehyde (6.8 g, 20.5mmol) overnight. After concentration, the residue was purified by silicagel chromatography to provide 4.24 g (72%) of the unsaturated aldehydeas a pale yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H),1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16 (s, 3H), 3.67-3.76 (m, 2H), 3.74(s, 3H), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 6.40-6.48 (m, 1H), 9.2 (s,1H).

The trimethylsilyethyl protected aldehyde is treated withdiethylphosphite in a solvent such as acetonitrile in the presence of abase such as triethylamine to afford the hydroxy phosphonate, accordingto a procedure such as that reported in Tetrahedron, 1995, 51, 2099. Thehydroxy phosphonate is O-akylated and then the protecting group isremoved by treatment with either trifluoroacetic acid ortetrabutylammonium fluoride to generate the desired methoxy phosphonateanalog.

Alternatively, the aldehyde is mixed with diethyl(2-aminoethyl)phosphonate and treated with a reducing agent such assodium triacetoxyborohydride to generate the amino phosphonate analog.

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution ofCeCl₃ (0.68 mL, MeOH: H₂O, 9:1) was added, followed by LiBH₄ (0.14 mL,0.28 mmol of a 2M solution in THF). The ice bath was removed and thereaction mixture was allowed to warm to room temperature. The reactionmixture was stirred for an additional 40 minutes whereupon TLC indicatedcomplete consumption of starting aldehyde. The reaction was worked up byaddition of aqueous 1N HCl (0.5 mL) and the product was extracted withCH₂Cl₂. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layer was concentrated underreduced pressure and the residue was purified by silica gelchromatography to provide 100 mg (97%) of the product as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81(s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H),4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H).

Polymer-supported triphenylphosphine is soaked in DCM for 1 hour. Theallylic alcohol and carbon tetrabromide are sequentially added. When thereaction is complete, the mixture is filtered and the filtrateconcentrated. The bromide is purified as necessary by chromatography.

The allylic bromide is treated in an inert organic solvent such asdimethylformamide with an alkali metal salt of ethyldiethoxyphosphorylacetate (prepared by reacting ethyldiethoxyphosphorylacetate with sodium hexamethyldisilazide or sodiumhydride) to afford the ethoxycarbonyl phosphonate, according to aprocedure such as that described in WO 9522538. The carboxylic estergroup is converted to both the carboxylic amide and the hydroxymethylgroups according to the methods conventionally utilized for amideformations and ester reductions. For example, the carboxylic ester issaponified with aqueous lithium hydroxide. The acid is activated withethyl chloroformate and reduced with sodium borohydride to generate,after removal of the protecting group, the hydroxymethyl phosphonateanalog. The acid is also converted to its acyl chloride and then reactedwith ethylamine to afford the amide analog.

The aryl acetaldehyde is coupled with 2-(diethoxyphosphoryl)-but-3-enoicacid ethyl ester to generate the 2-vinyl substituted ester, according toa procedure such as that reported in Synthesis, 1999, 282. The 2-vinylgroup is converted to the 2-cyclopropyl group under cyclopropanationconditions such as those described in Tetrahedron Lett. 1998, 39, 8621.The ester is converted to the alcohol, which, optionally, can be furthersubjected to reactions such as that described below to generate variousphosphonate-containing mycophenolic acid analogues.

The allylic alcohol is treated with bromomethylphosphonic aciddiisopropyl ester in the presence of a base such as lithium t-butoxidein a solvent such as dimethylformamide. The phenol protecting group isthen removed by treatment with trifluoroacetic acid.

The phenacetaldehyde can alternatively be converted to the allylphosphonium salt, according to a procedure such as that reported in J.Org. Chem. 1987, 52, 849. The phosphonium salt is then treated with thecommercially available 3,3,3-trifluoro-2-oxo-propionic acid ethyl esterand a base such as sodium hydride to generate the 2-trifluoromethylsubstituted ester. The ester is converted to the alcohol, which,optionally, can be further subjected to reactions described earlier togenerate mycophenolic acid analogues with various side chains containingthe phosphonate group.

Introduction of R₄ Variants

The enone (synthesis reviewed in Tetrahedron, 1985, 41, 4881-4889) andthe diene (Chem. Pharm. Bull., 1989, 37, 2948-2951) are dissolved in anorganic solvent such as toluene, stirred at room temperature for 24hours and heated to reflux for additional 5 hours, according to aprocedure from J. Med. Chem., 1996, 39, 4181-4196. The reaction mixtureis cooled to room temperature and the solvent removed in vacuo. Thecrude reaction product is further purified by chromatography.

The product of step one is dissolved in an organic solvent such as DCMand m-chloroperbenzoic acid is added, according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, thesolution is poured into aqueous sodium hydrogen sulfite solution. Theorganic layer is washed with saturated aqueous sodium bicarbonatesolution and is dried over sodium sulfate. Filtration and evaporation ofsolvents yields the crude product.

The crude product is dissolved in an organic solvent such as toluene andtreated with dichlorodicyanoquinone (DDQ), according to a procedure fromJ. Med. Chem., 1996, 39, 4181-4196. At the end of the reaction thesolvent is removed in vacuo and the crude material is further purifiedby chromatography.

The product is dissolved in an organic solvent such as DCM and treatedwith boron trichloride at reflux temperature, according to a modifiedprocedure from J. Med. Chem., 1996, 39, 46-55. At the end of thereaction the solution is washed with aqueous HCl solution. The solutionis dried over sodium sulfate. Removal of the solvent yields the crudereaction product. Further purification is achieved by chromatography.

The product of the previous step and triphenylphosphine are dissolved inan organic solvent such as tetrahydrofuran (THF).Diisopropylazodicarboxylate (DIAD) is added dropwise at 0° C. Stirringis continued. A solution of 2-trimethylsilyl ethanol in THF is added andstirring is continued. At the end of the reaction, the solvent isremoved in vacuo. The crude reaction solid is extracted with a mixtureof organic solvents such as hexanes and diethylether. The washings arecombined and the solvents removed in vacuo. The desired product isfurther purified and separated from the undesired regioisomer bychromatography.

The starting material is dissolved in an organic solvent such asdimethylformamide (DMF) and reacted with N-chlorosuccinimide, accordingto a procedure from J. Med. Chem., 1996, 39, 4181-4196. After thestarting material is consumed the reaction mixture is poured into waterand the product is extracted with diethyl ether. The combined organiclayers are dried over sodium sulfate. Filtration and evaporation of thesolvents yields the crude product. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as benzeneand reacted with dimethyl sulfoxide (DMSO), dicyclohexylcarbodiimide(DCC), and orthophosphoric acid according to a procedure from J. Am.Chem. Soc., 1966, 88, 5855-5866. At the end of the reaction, thesuspension is filtered and the organic layer washed with aqueous sodiumbicarbonate solution and dried over sodium sulfate. Filtration andevaporation of solvents yields the crude material. Further purificationis achieved by chromatography.

The product of step one is dissolved in an organic solvent such as DCMor THF and treated with Raney nickel, according to procedures reviewedin Chem. Rev., 1962, 62, 347-404. When all starting material isconsumed, the reaction is filtered and the solvent removed in vacuo.Further purification is achieved by chromatography.

The starting material is dissolved in an organic solvent such as DCM andbromine is added, according to a procedure from J. Med. Chem., 1996, 39,4181-4196. At the end of the reaction, additional DCM is added and thesolution washed with aqueous sodium thiosulfate solution and brine. Theorganic layer is dried over sodium sulfate. Filtration and evaporationof solvents yields the crude material. Further purification is achievedby chromatography on silica gel.

The starting material, lithium chloride, triphenylarsine,tributylvinyltin, andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct are heated inan organic solvent such as N-methylpyrrolidinone at an elevatedtemperature of approximately 55° C., according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, the mixtureis cooled to room temperature and poured into a mixture of ice,potassium fluoride, water, and ethyl acetate. Stirring is continued for1 hour. The suspension is filtered through Celite and extracted withethyl acetate. The combined organic extracts are dried over sodiumsulfate. The solvents are removed in vacuo and the crude material isfurther purified by chromatography.

The product of step two is dissolved in a mixture of organic solventssuch as benzene and ethyl acetate. Tris(triphenylphosphine)rhodium(I)chloride is added and the reaction is placed under an atmosphere ofhydrogen, according to a procedure from J. Med. Chem., 1996, 39,4181-4196. The solvents are removed in vacuo and the crude reaction isfiltered through silica gel. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as DMF.Potassium carbonate and allyl bromide are added and stirring at roomtemperature is continued, according to a procedure from J. Med. Chem.,1996, 39, 4181-4196. After all the starting material is consumed,aqueous HCl solution and diethyl ether are added and the organic layeris collected and the solvent is removed in vacuo.

The crude material is dissolved in N,N diethylaniline and the reactionmixture is heated at an elevated temperature of ca. 180° C. At the endof the reaction, the mixture is cooled to room temperature and pouredinto a mixture of aqueous HCl (2N) and ethyl actetate. The organic layeris washed with aqueous HCl (2N) and dried over sodium sulfate.Filtration and removal of the solvents yields the crude product. Furtherpurification is achieved by chromatography.

The product of step 2 is dissolved in a mixture of organic solvents suchas methanol, DCM, and pyridine. The solution is cooled to −78° C. andozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The aldehyde is dissolved in an organic solvent such as THF and isreacted with triphenylphosphonium sec.propyl bromide and potassiumtert.butoxide, according to procedures reviewed in Chem. Rev., 1989, 89,863-927. At the end of the reaction, the solvent is removed in vacuo andthe crude material purified by chromatography.Introduction of Linkers to Phosphonates

The phenols shown herein may optionally be alkylated with the reagent ofchoice. Optionally, the phosphonate moiety will be part of such areagent. Alternatively, it will be introduced in a subsequent step by avariety of means, of which three are illustrated above. For example, analkyl halide may be heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., “Synthesisof Carbon-phosphorus Bonds,” CRC press, 1988). Alternatively, an epoxidemay be reacted with the anion of a dialkyl phosphinate. In a furtherexample, the phosphonate reagent may be the electrophile, e.g., anacetylide anion may be condensed with phosphorus oxychloride and theintermediate dichlorophosphonate quenched with ethanol to generate thediethyl ester of the desired phosphonic acid.

EXAMPLE 292 Preparation of Representative Celecoxib Compounds of theInvention

Specific compounds of the invention can be prepared as illustrated asfollows.

Reagents & Conditions: (a) PMBCl, K₂CO₃, acetone, rt; (b) (i) CF₃COOEt,NaH, THF, −20° C.-rt; (ii) 4-sulfonamidophenylhydrazine, EtOH, reflux,overnight; (c) Cs₂CO₃, DMF, 0° C.-rt.

Synthesis of Compound 292.2.

4-Hydroxyacetophenone (1.6 g, 11.02 mmol) was dissolved in dry acetone(15 mL) under an argon atmosphere, and p-methoxybenzyl chloride (1.42mL, 12.12 mmol) was added, followed by powdered K₂CO₃ (2.28 g, 16.53mmol) at room temperature. The reaction mixture was stirred overnightand solids were filtered off. The filtrate was concentrated to a syrup,dissolved in 20 mL of CHCl₃ and washed with deionized water (2×5 mL).The organic layer was dried over Na₂SO₄, concentrated and purified bysilica gel column chromatography (cyclohexane: EtOAc, 2:1) to affordpure compound 292.2 as semi-solid (600 mg, 22%). ESI-MS: m/z 257 [M+H]⁺.

Synthesis of Compound 292.3.

Step 1. Compound 292.2 (100 mg, 0.39 mmol) was dissolved in dry THF (3mL) and cooled to −20° C. NaH (24 mg, 0.98 mmol) was added. The mixturewas stirred for 5 minutes and ethyl trifluoroacetate (56 μL, 0.47 mmol)was added at −20° C. The mixture was allowed to warm to room temperaturewith stirring for 24 hours. After cooling to 0° C., MeOH (2 mL) wasadded and the mixture was concentrated to a syrup, which was dissolvedin 10 mL of CHCl₃ and washed with 1N HCl (5 mL) and deionized water (5mL). The organic layer was dried over Na₂SO₄ and concentrated to give alight yellow semi-solid compound (130 mg) that was used without furtherpurification.

Step 2. The crude product from Step 1 (130 mg, 0.37 mmol) was dissolvedin absolute ethanol (10 mL). 4-Sulfonamidophenylhydrazine hydrochloride(105 mg, 0.56 mmol) was added, and the reaction mixture was heated atreflux overnight, after which TLC (Cyclohexane:EtOAc, 2:1) showedcomplete consumption of starting material. The mixture was cooled,concentrated to a syrup, dissolved in 20 mL of EtOAc, washed withdeionized water (2×5 mL), dried over Na₂SO₄ and concentrated to give ayellow syrup. Purification by silica gel column chromatography(cyclohexane: EtOAc, 2:1) afforded the compound as light yellow solid(123 mg, 66%). HPLC: 98.6% pure (Sphereclone 5 μL, H₂O: MeCN, 20 minlinear from 10-90% MeCN, 1.0 mL/min). ESI-MS: m/z 384 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆, D₂O exchanged): δ 7.88-7.85 (2H, m, ArH), 7.54-7.50(2H, m, ArH), 7.13-7.09 (3H, m, ArH), 6.79-6.75 (2H, m, ArH).

Synthesis of Compound 292.4.

Compound 292.3 (70 mg, 0.14 mmol) was dissolved in 3 mL of dry DMF underan argon atmosphere. Diethylphosphonomethyl-O-triflate (51 mg, 0.17mmol) and Cs₂CO₃ (69 mg, 0.21 mmol) were added. The reaction mixture wasstirred overnight at room temperature. Deionized water (10 mL) was addedand the mixture was extracted with ethyl acetate (2×15 mL). The ethylacetate layer was washed with 1N HCl (5 mL) and deionized water (10 mL)and dried over Na₂SO₄. Concentration gave a syrup that on purificationby preparative-TLC (1 plate, 20×20 cm, 2000 microns, solvent:CHCl₃:MeOH, 95:5) gave a gummy yellow solid (20 mg, 27% yield). HPLC:97.8% pure (Sphereclone 5 μL, H₂O: MeCN, 20 min linear from 10-90% MeCN,1.0 mL/min). ESI-MS: m/z 534 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.91(2H, d, J=8.8 Hz, ArH), 7.46 (2H, d, J=8.8 Hz, ArH), 7.16 (2H, d, J=8.9Hz, ArH), 6.96 (2H, d, J=8.9 Hz, ArH), 6.73 (1H, s, CH), 5.07 (2H, br s,NH), 4.31-4.22 (6H, m, 3×OCH₂), 1.37 (6H, t, J=7.1 Hz, 2×CH₃). ³¹P NMR(CDCl₃, H₃PO₄ as external reference): δ 19.14

EXAMPLE 293 Preparation of Representative Triamcinolone AcetonideDerivatives

The syntheses of the phosphonate compounds of this invention, and of theintermediate compounds involved in their synthesis, is described below.

Protection of Reactive Substituents.

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the described reaction, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis (Second Edition, Wiley, 1991). The protection anddeprotection of steroidal ketones and alcohols is described in J. Friedand J. A. Edwards, Organic Reactions in Steroid Chemistry, Vol. 1 375ff(van Nostrand Reinhold, 1972). Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc.

For example, a protection-deprotection sequence is depicted above inwhich the 20-ketone group and/or the 21-hydroxyl group of Triamcinoloneacetonide 293.1 are protected to afford the derivative 293.2. The ketoneis protected, for example, by conversion to the cyclic ethylene ketal,by reaction in toluene solution at reflux temperature with ethyleneglycol and an acid catalyst, as described in J. Am. Chem. Soc., 77:1904(1955). Deprotection is effected by reaction with pyridinium tosylate inaqueous acetone, as described in J. Chem. Soc. Chem. Comm. 1351 (1987).

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 293.1 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn. 50:102 (1970). The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc. 101:5841 (1979).

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 293.1 is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc. Chem. Comm. 406(1983), to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The 21-hydroxyl group is protected, for example, by conversion to theacetate ester by reaction with one molar equivalent of acetyl chloridein dichloromethane/pyridine. The 21-acetoxy group is removed by reactionwith one molar equivalent of lithium hydroxide in aqueousdimethoxyethane.

Alternatively, the 21-hydroxyl group is protected by conversion to thetert.butyl dimethylsilyl ether, by reaction in dimethylformamidesolution with one molar equivalent of tert.butylchlorodimethylsilane andimidazole, as described in J. Am. Chem. Soc., 94: 6190, 1972. The silylether is removed by reaction with tetrabutylammonium fluoride intetrahydrofuran solution, as described in J. Am. Chem. Soc. 94:6190(1972).

The protected compound 293.2 is then converted into thephosphonate-containing analog 293.3, using the procedures describedbelow, and the protecting group or groups are then removed, as describedabove, to give the phosphonate 293.4.

EXAMPLE 294 Preparation of Representative Triamcinolone AcetonideDerivatives

The preparation of phosphonates of compounds of the invention in whichthe phosphonate is attached by means of an imino or iminoxy group and avariable carbon chain is shown above.

In this procedure, the ketone-protected derivative 294.1 is reacted withan amine or hydroxylamine 294.2, in which R² is an alkyl, alkenyl,cycloalkyl or cycloalkenyl group, optionally incorporating a heteroatomO, S or N, or a functional group such as an amide, ester, oxime,sulfoxide or sulfone, etc., or an optionally substituted aryl,heteroaryl or aralkyl group, optionally incorporating a heteroatom O, Sor N, and X is either a phosphonate group or a group that issubsequently converted into a phosphonate-containing substituent. Forexample, X may be dialkylphosphono, bromo, hydroxy, amino, carboxy andthe like.

The reaction is conducted between equimolar amounts of the reactants inan aprotic solvent such as pyridine or xylene, or in an alcoholicsolvent such as ethanol, optionally in the presence of an acid catalyst,to give the imine or oxime 294.3. The preparation of oximes of steroidal3-ketones is described in Anal. Bioch. 86:133 (1978) and in J. Mass.Spectrom. 30:497 (1995). The protecting group is then removed, asdescribed in Example 171, to afford the 20-keto phosphonate product294.4.

Also illustrated above is the preparation of hydroxylamine ethersincorporating a phosphonate group. In this procedure, a phosphonate294.5, in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 294.6(Aldrich) to produce the ether 294.7. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 294.8. The above procedure is also employed for the preparation ofsubstituted hydroxylamines which are precursors to phosphonates.

The preparation of specific compounds of the invention is shown above.

In particular, the preparation of phosphonates of the invention in whichthe phosphonate is attached by means of an iminoxy group is shown. Inthis procedure, the substrate 294.1, in which the 20-ketone is protectedas the dimethyl hydrazone derivative, is reacted with a dialkylphosphonomethyl hydroxylamine 294.8a, prepared as described above from adialkyl trifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett.27:1477 (1986)) and BOC-hydroxylamine, to afford the oxime 294.10.Deprotection, as described herein, e.g., in Example 171, then affordsthe 20-keto phosphonate 294.11. The oxime forming reaction is performedat ambient temperature in ethanol-acetic acid solution between equimolaramounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 294.8a, different oxime ethers 294.2, the corresponding products294.4 are obtained.

Synthesis of specific compounds of the invention is illustrated above.In particular, the preparation of compounds of the invention in whichthe phosphonate group is attached by means of a thienylethoxy oximegroup is shown. In this procedure, the dienone 294.1, in which the20-ketone is protected as the dimethyl hydrazone, is reacted, asdescribed above, with O-(5-bromo-2-thienylethoxy)hydroxylamine 294.9,prepared as described above from 5-bromo-2-thienylethyl bromide (Syn.,2003, 455), and BOC-protected hydroxylamine 294.6, to give the oxime294.12. The protecting group is then removed to yield the 20-ketoproduct 294.13. The latter product is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite 294.14 to afford thephosphonate 294.15. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem. 35:1371 (1992). The reaction is performed atca. 100° in an inert solvent such as toluene, in the presence of a basesuch as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 294.13 is coupled with a dialkyl vinylphosphonate 294.16 (Aldrich) to afford the phosphonate 294.17. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res. 12:146(1979). The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenylphosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 294.17 isreduced, for example by reaction with diimide, to produce the saturatedanalog 294.18. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromothienylethyl reagent 294.9, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 294.15, 294.17 and294.18 are obtained.

The preparation of phosphonates of the invention in which thephosphonate is attached by means of a 2-phenylimino group is illustratedabove. In this procedure, the substrate 294.1, in which the 20-ketone isprotected as the dimethylhydrazone, is reacted with a dialkyl2-aminophenyl phosphonate 294.20 (Syn., 1999, 1368), to give, afterdeprotection, the imine product 294.21. The imine forming reaction isconducted in a hydrocarbon solvent such as toluene or xylene, at refluxtemperature, in the presence of a basic catalyst such as sodiummethoxide, or an acid catalyst such as p-toluenesulfonic acid, underazeotropic conditions.

Using the above procedures, but employing, in place of the 2-aminophenylphosphonate 294.20 different amino-substituted aryl or heteroarylphosphonates, products analogous to 294.21 are obtained.

Illustrated above is the preparation of phosphonates of the invention inwhich the phosphonate is attached by means of an oximino group and anether linkage. In this procedure, the dienone 294.1, in which the20-ketone is protected as the dimethylhydrazone, is reacted withhydroxylamine 294.22 to yield the oxime 294.23. The reaction ofsteroidal 1,4-dien-3-ones with hydroxylamines is described in J. SteroidBioch. 7:795 (1976). The reaction is performed between equimolar amountsof the reactants in a polar organic solvent such as pyridine ormethanol, optionally in the presence of acetic acid or sodium acetate.

The product 294.23 is then coupled, in a Mitsonobu reaction, with adialkyl 4-hydroxyphenyl phosphonate 294.24 (Epsilon), to yield, afterdeprotection, the ether oxime 294.25. The preparation of aromatic ethersby means of the Mitsonobu reaction is described, for example, in R. C.Larock, Comprehensive Organic Transformations 448 (VCH, 1989), in F. A.Carey and R. J. Sundberg, Advanced Organic Chemistry, Part B 153-4(Plenum, 2001), and in Org. React. 42:335, (1992). The phenol and thehydroxyl component are reacted together in an aprotic solvent such as,for example, tetrahydrofuran, in the presence of a dialkylazodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.42:335-656 (1992).

Using the above procedures, but employing, in place of thehydroxyaryl-substituted phosphonate 294.24, differenthydroxyaryl-substituted phosphonates, the products analogous to 294.25are obtained.

EXAMPLE 295 Preparation of Representative Triamcinolone AcetonideDerivatives

Illustrated above is the preparation of phosphonate esters of theinvention in which the phosphonate group is attached to the 1′ or 2′position of the pyrazole ring, by means of an aromatic or heteroaromaticgroup, a heteroatom and/or a variable carbon chain. In this procedure,the dienone 293.1, in which the 21-hydroxyl group is protected asdescribed in Example 293, is reduced to afford the 1,2-dihydro product295.1. The catalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem. 44:602 (2001). The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc. 86:1520(1964), to afford the 2-formyl product 295.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 295.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X may be dialkylphosphono, bromo, hydroxy, amino, carboxyland the like. The reaction yields, after deprotection of the 21-hydroxylgroup, the isomeric 2′- and 1′-aryl pyrazoles 295.4 and 295.5. Thepyrazole-forming reaction is performed between equimolar amounts of thereactants in an acidic solvent such as acetic acid, as described in J.Am. Chem. Soc. 86:1520 (1964). The pyrazoles 295.4 and 295.5 are thentransformed, for example by the procedures described herein, into thephosphonates 295.6 and 295.7.

The preparation of specific compounds of the invention in which thephosphonate is attached by means of an ether or an acetylenic linkage isshown above.

In this procedure, the ketoaldehyde 295.2 is reacted, as describedabove, with 3-hydroxyphenyl hydrazine 295.8 (JP 03011081) to give thepyrazoles 295.9a and 295.10. The 2′-substituted isomer 295.9a is thenreacted in dichloromethane solution with one molar equivalent oftrifluoromethanesulfonyl chloride and pyridine, to give the triflate295.9b. The product is then reacted in toluene solution with a dialkylpropynyl phosphonate 295.11 (Syn 1999, 2027), triethylamine and acatalytic amount of tetrakis(triphenylphosphine)palladium (0), to givethe acetylenic product 295.12. The palladium-catalyzed coupling reactionof aryl triflates with terminal acetylenes is described in WO 0230930.

The isomeric pyrazole 295.10 is reacted, in dimethylformamide solutionat 70°, with one molar equivalent of a dialkyl 2-bromoethyl phosphonate295.13 (Aldrich) and potassium carbonate to yield the ether phosphonate295.14.

Using the above procedures, but employing different hydroxy-substitutedhydrazines, and/or different acetylenic or bromo-substitutedphosphonates, products analogous to 295.12 and 295.14 are obtained.

The preparation of phosphonates of the invention in which thephosphonate group is attached by means of a phenyl group or aphenylcyclopentenyl linkage is shown above. In this procedure, theketoaldehyde 295.2 is reacted, as described above, with 4-bromophenylhydrazine 295.15 (J. Organomet. Chem., 62:581(1999)) to produce thepyrazoles 295.16 and 295.17. The 2′-substituted isomer 295.16 is thencoupled, as described above, with a dialkyl phosphite 295.18 to give thephosphonate 295.19.

Alternatively, the 1-substituted pyrazole 295.22 is coupled in a Heckreaction, as described above, with a dialkyl cyclopentenyl phosphonate295.20 (Syn. Comm., 28:83(1998)) to prepare the cyclopentenylphosphonate 295.21.

Using the above procedures, but employing, in place of the 4-bromophenylhydrazine 295.15, different bromo-substituted hydrazines, and/ordifferent dialkyl alkenyl-substituted phosphonates, the productsanalogous to the compounds 295.19 and 295.21 are obtained.

EXAMPLE 296 Preparation of Representative Triamcinolone AcetonideDerivatives

The preparation of phosphonate esters of the invention in which thephosphonate group is attached by means of a variable carbon linkage isillustrated above.

In this procedure, the ketoaldehyde 295.2 is reacted with hydrazine toafford the pyrazole derivative 296.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,86:1520 (1964). The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 296.2, in which R² and X are as defined above, or a reactivebromoheteroaromatic reagent, to yield the alkylation products 296.3 and296.4. The alkylation of substituted pyrazoles is described, forexample, in T. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992).The reaction is performed between equimolar amounts of the substrates ina polar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as dimethylaminopyridine, lithiumhexamethyldisilazide and the like. The products 296.3 and 296.4 are,except in cases where X is dialkylphosphono, converted into thephosphonates 296.5 and 296.6, using the procedures described herein.

Specific compounds of the invention are shown above. The pyrazole 296.1is reacted in dimethylformamide solution at 70° with one molarequivalent of a dialkyl 4-bromobutyl phosphonate 296.7 (Synthelec) andcesium carbonate, to give the pyrazoles 296.8 and 296.9.

Using the above procedures, but employing different bromo-substitutedphosphonates, the products analogous to 296.8 and 296.9 are obtained.

Specific compounds of the invention are shown above. The pyrazole 296.1is reacted in tetrahydrofuran solution with 1,4-dibromobut-2-yne 296.10and potassium hexamethyl disilazide, to give the alkylation products296.11 and 296.12. The 2′-substituted isomer 296.11 is then reacted, ina Arbuzov reaction, with a trialkyl phosphite to yield the phosphonate296.13. The Arbuzov reaction is described in Handb. OrganophosphorusChem., 115 (1992). In this procedure, in which a bromo substituent isconverted into the corresponding phosphonate, the substrate is heated atfrom about 60° to about 160° with a five to fifty-fold molar excess of atrialkyl phosphite, to effect the transformation.

The 2′-substituted pyrazole 296.14 is reacted at 70° indimethylformamide solution with one molar equivalent of a dialkylhydroxymethyl phosphonate 296.14 (Aldrich) and cesium carbonate, to givethe ether phosphonate 296.15.

Using the above procedures, but employing different dibromides, and/ordifferent hydroxyl-substituted phosphonates, the products analogous to296.13 and 296.15 are obtained.

EXAMPLE 297 Preparation of Representative Mometasone Furoate Derivatives

Preparation of representative compounds of the invention is describedhereinbelow.

Protection of Reactive Substituents

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the described sequence is reacted, and to deprotectthe substituents afterwards, according to the knowledge of one skilledin the art. Protection and deprotection of functional groups aredescribed, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990. The protectionand deprotection of steroidal ketones and alcohols is described inOrganic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J. A.Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactive substituentswhich may be protected are shown in the accompanying schemes as, forexample, [OH], [O], etc.

For example, depicted above is a protection-deprotection sequence inwhich the steroid side-chain is protected as a bis-methylenedioxy (BMD)moiety. In this sequence,9α-chloro-16α-methyl-11β,17α,21-trihydroxypregn-1,4-dien-3,21-dione297.1 (U.S. Pat. No. 4,472,393) is reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in “ProtectiveGroups in Organic Synthesis,” by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative 297.2.

The phosphonate moiety is then introduced, using the proceduresdescribed below, to produce the phosphonate ester 297.3. The BMD moietyis then hydrolyzed, for example by treatment with 50% aqueous aceticacid, as described in “Protective Groups in Organic Synthesis,” by T. W.Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to affordthe triol 297.4. The latter compound is then converted into the17,21-cyclic orthoester 297.6 using the procedure described in Chem.Pharm. Bull., 34:1613(1986). The substrate is reacted indimethylformamide at 70° C. with two molar equivalents of triethylortho-2-furoate 297.5 (Zh. Org. Khim., 50:1348(1980)) and a catalyticamount of p-toluenesulfonic acid. The product is then reacted with anexcess of trimethylsilyl chloride in dimethylformamide at ambienttemperature to produce the 21-chloro 17-(2-furoate) product 297.7.

Alternatively, the substrate 297.4 is converted into the product 297.7by means of the method described in J. Med. Chem., 1987, 30:1581(1987).In this procedure, the 21-hydroxy group is activated by conversion tothe 21-mesylate, by reaction with mesyl chloride in pyridine; themesylate group is then displaced to yield the 21-chloro intermediate, byreaction with lithium chloride in dimethylformamide, and the 17-hydroxylgroup is esterified to give the 21-chloro-17-(2-furoate) derivative297.7. The selective acylation of the 17α-hydroxyl group in the presenceof an 11β hydroxyl group is described in J. Med. Chem., 30:1581(1987).

EXAMPLE 298 Preparation of Representative Mometasone Furoate Derivatives

The preparation of phosphonates of the invention in which thephosphonate is attached by means of an imino or iminoxy group and avariable carbon chain is illustrated above.

In this procedure, the BMD-protected derivative 297.2 is reacted with anamine or hydroxylamine 298.1, in which R² is an alkyl, alkenyl,cycloalkyl or cycloalkenyl group, optionally incorporating a heteroatomO, S or N, or a functional group such as an amide, ester, oxime,sulfoxide or sulfone, etc., or an optionally substituted aryl,heteroaryl or aralkyl group, optionally incorporating a heteroatom O, Sor N, and X is either a phosphonate group or a group that issubsequently converted into a phosphonate-containing substituent. Forexample, X may be dialkylphosphono, bromo, hydroxy, amino, carboxy andthe like. The reaction is conducted between equimolar amounts of thereactants in an aprotic solvent such as pyridine or xylene, or in analcoholic solvent such as ethanol, optionally in the presence of an acidcatalyst, to give the imine or oxime. The preparation of oximes ofsteroidal 3-ketones is described in Anal. Bioch., 86:133(1978). and inJ. Mass. Spectrom., 30:497(1995). The BMD-protected side-chain compound298.2 is then converted into the triol 298.3a, and then to the 21-chloro17-(2-furoate) product 298.3b, as described herein.

Also illustrated above is the preparation of hydroxylamine ethersincorporating a phosphonate group. In this procedure, a phosphonate298.4, in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 298.5(Aldrich) to produce the ether 298.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 298.7.

The synthesis of specific compounds of the invention is shown above. Thepreparation of phosphonates of the invention in which the phosphonate isattached by means of an iminoxy group is illustrated. In this procedure,the substrate 297.2 is reacted with a dialkyl phosphonomethylhydroxylamine 298.8, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 27:1477(1986))and BOC-hydroxylamine, to afford the oxime 298.9. Deprotection thenaffords the triol 298.10a from which the 21-chloro 17-(2-furoate)compound 298.10b is prepared, using the procedures described in Example297. The oxime forming reaction is performed at ambient temperature inethanol-acetic acid solution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 298.8, different oxime ethers 298.1, the corresponding products298.3b are obtained.

The synthesis of specific compounds of the invention is shown above. Thepreparation of compounds of the invention in which the phosphonate groupis attached by means of a pyridylmethoxy oxime group is illustratedabove. In this procedure, the dienone 297.2 is reacted, as describedabove, with O-(5-bromo-3-pyridylmethoxy)hydroxylamine 298.11, preparedas described above from 5-bromo-3-bromomethylpyridine (EP 511865) andBOC-protected hydroxylamine 298.5, to give, after deprotection of theside-chain, the oxime 298.12. The product is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphite 298.13 toafford the phosphonate 298.14a. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem., 35: 1371(1992). The reactionis performed at ca. 100° C. in an inert solvent such as toluene, in thepresence of a base such as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0). The 21-hydroxy compound298.14a is then converted, as described in Example 297, into the21-chloro 17-(2-furoate) derivative 298.14b.

Alternatively, the bromo compound 298.12 is coupled with a dialkyl vinylphosphonate 298.15 (Aldrich) to afford the phosphonate 298.16a. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in F. A. Carey and R. J. Sundberg, “AdvancedOrganic Chemistry,” 503ff (Plenum, 2001) and in Acc. Chem. Res., 12:146(1979). The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenylphosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethyl amine or potassium carbonate.Optionally, the double bond present in the product 298.16a is reduced,for example by reaction with diimide, to produce the saturated analog298.17a. The reduction of olefinic bonds is described in R. C. Larock,“Comprehensive Organic Transformations,” 6ff (VCH, 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample, using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane. The products 298.16a and298.17a are then converted into the 21-chloro 17-(2-furoate) analogs298.16b and 298.17b.

Using the above procedures, but employing, in place of thebromopyridylmethoxy reagent 298.11, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 298.14b, 298.16band 298.17b are obtained.

The preparation of specific compounds of the invention is depictedabove. The preparation of phosphonates of the invention in which thephosphonate is attached by means of an imino group. In this procedure,the substrate 297.2 is reacted with a dialkyl 4-aminophenyl phosphonate298.18 (Epsilon) to give, after deprotection, the imine product 298.19a.The imine forming reaction is conducted in a hydrocarbon solvent such astoluene or xylene, at reflux temperature, in the presence of a basiccatalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions. The product is thenconverted into the 21-chloro 17-(2-furoate) compound 298.19b.

Using the above procedures, but employing, in place of the 4-aminophenylphosphonate 298.18 different amino-substituted aryl or heteroarylphosphonates, products analogous to 298.19b are obtained.

The preparation of specific compounds of the invention is shown above.Phosphonates of the invention in which the phosphonate is attached bymeans of an oximino group and an amine linkage are illustrated. In thisprocedure, the dienone 297.2 is reacted withO-(2-aminoethyl)hydroxylamine 298.20 (Pol. J. Chem., 55:1163(1981)) toyield the oxime 298.21. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch.,7:795(1976); the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The productis then reacted, in a reductive amination procedure, with a dialkyl4-formylphenyl phosphonate 298.22 (Epsilon) and sodiumtriacetoxybrorhydride, to yield the amine oxime 298.23. The preparationof amines by means of reductive amination procedures is described, forexample, in R. C. Larock, “Comprehensive Organic Transformations,” 421(VCH), and in F. A. Carey and R. J. Sundberg, “Advanced OrganicChemistry,” Part B, 269 (Plenum, 2001). In this procedure, the aminecomponent and the aldehyde or ketone component are reacted together inthe presence of a reducing agent such as, for example, borane, sodiumcyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminumhydride, optionally in the presence of a Lewis acid, such as titaniumtetraisopropoxide, as described in J. Org. Chem., 55:2552 (1990).

The amine product 298.23 is then converted, as described in Example 297,into the 21-chloro 17-(2-furoate) product 298.24b.

Using the above procedures, but employing, in place of the hydroxylamine298.22, different amino-substituted hydroxylamines, and/or differentformyl-substituted phosphonates, the products analogous to 298.24b areobtained.

EXAMPLE 299 Preparation of Representative Mometasone Furoate Derivatives

The preparation of phosphonate esters of the invention in which thephosphonate group is attached to the 1′ or 2′ position of the pyrazolering, by means of an aromatic or heteroaromatic group, a heteroatomand/or a variable carbon chain is illustrated above.

In this procedure, the BMD-protected dienone 297.2 is reduced to affordthe 1,2-dihydro product 299.1. The catalytic hydrogenation reaction iseffected by the use of tris(triphenylphosphine)rhodium (I) chloride, forexample as described in J. Med. Chem., 44:602(2001). The product is thenreacted with ethyl formate and a base such as sodium hydride, in aninert solvent such as toluene or dimethylformamide, as described in J.Am. Chem. Soc., 86:1520(1964), to afford the 2-formyl product 299.2.This compound is then reacted with an alkyl, aralkyl, aryl or heteroarylhydrazine 299.3, in which the substituent X is either a phosphonategroup or a group that is subsequently transformed into aphosphonate-containing substituent. For example, X may bedialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. Thereaction yields the isomeric 2′- and 1′-aryl pyrazoles 299.4 and 299.5.The pyrazole-forming reaction is performed between equimolar amounts ofthe reactants in an acidic solvent such as acetic acid, as described inJ. Am. Chem. Soc., 86:1520(1964). The pyrazoles 299.4 and 299.5 are thentransformed, for example, by the procedures described herein, via theBMD-protected intermediates 299.6 and 299.7, into the 21-chloro17-(2-furoate) phosphonates 299.8b and 299.9b.

The preparation of specific compounds of the invention is depictedabove. Phosphonates of the invention in which the phosphonate isattached by means of a benzyl linkage are shown above. In thisprocedure, the ketoaldehyde 299.2 is reacted, as described above, with4-bromobenzyl hydrazine 299.10 (Ann., 717:104(1968)) to give thepyrazoles 299.11 and 299.12. The 2′-substituted isomer 299.11 is thencoupled, as described in Example 298, with a dialkyl phosphite, to yieldthe phosphonate 299.14. The BMD protecting group is then removed and theproduct is converted into the 21-chloro 17-(2-furoate) product 299.16b.

The isomeric pyrazole 299.12 is subjected to the same series ofreactions to afford the isomeric product 299.19b.

Using the above procedures, but employing different bromo-substitutedhydrazines, the products analogous to 299.16b and 299.19b are obtained.

The preparation of specific compounds of the invention is shown above.Phosphonates of the invention in which the phosphonate group is attachedby means of a phenyl group and an ether or thioether linkage. In thisprocedure, the ketoaldehyde 299.2 is reacted, as described above, with4-hydroxyphenyl hydrazine 299.20 (EP 437105) to produce the pyrazoles299.21 and 299.22. The 1′-substituted isomer 299.21 is reacted indimethylformamide at 70° C., with a dialkyl 2-bromoethyl phosphonate299.23 (Aldrich) and potassium carbonate, to give the ether phosphonate299.24. The product is then deprotected to afford the triol 299.25awhich is converted into the 21-chloro 17-(2-furoate) compound 299.25b.

Alternatively, the 2′-substituted pyrazole 299.22 is coupled, in aMitsonobu reaction, with a dialkyl 2-mercaptoethyl phosphonate 299.26(Zh. Obschei. Khim., 43:2364(1973)) to prepare the thioether phosphonate299.27, which is deprotected, and the product is converted into the21-chloro 17-(2-furoate) analog 299.28b. The preparation of aromaticethers and thioethers by means of the Mitsonobu reaction is described,for example, in R. C. Larock, “Comprehensive Organic Transformations,”448 (VCH, 1989), and in F. A. Carey and R. J. Sundberg, “AdvancedOrganic Chemistry,” Part B, 153-4 (Plenum, 2001) and in Org. React.,42:335 (1992). The phenol and the alcohol or thiol component are reactedtogether in an aprotic solvent such as, for example, tetrahydrofuran, inthe presence of a dialkyl azodicarboxylate and a triarylphosphine, toafford the ether or thioether products. The procedure is also describedin Org. React., 42:335-656 (1992).

Using the above procedures, but employing, in place of the4-hydroxyphenyl hydrazine 299.20, different hydroxy-substitutedhydrazines, and/or different dialkyl bromo- or mercapto-substitutedphosphonates, the products analogous to the compounds 299.25b and299.28b are obtained.

EXAMPLE 300 Preparation of Representative Mometasone Furoate Derivatives

The preparation of the phosphonate esters of the invention is shownabove.

In this procedure, the ketoaldehyde 299.2 is reacted with hydrazine, toafford the pyrazole derivative 300.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,86:1520 (1964). The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 300.2, in which R² and X are as defined above, or a reactivebromoheteroaromatic reagent, to yield the alkylation products 300.3 and300.4. The alkylation of substituted pyrazoles is described, forexample, in T. L. Gilchrist, “Heterocyclic Chemistry,” 309 (Longman,1992). The reaction is performed between equimolar amounts of thesubstrates in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 300.3 and 300.4, except in cases where X is dialkylphosphono,are converted into the phosphonates 300.5 and 0.6, using the proceduresdescribed herein, and deprotection/chlorination/acylation then affordsthe 21-chloro 17-(2-furoate) compounds 300.7b and 300.8b.

The preparation of specific compounds of the invention is shown above.The pyrazole 300.1 is reacted with 2,5-dibromopyrimidine 300.9 (Chem.Lett., 583 (1992)) to give the pyrazoles 300.10 and 300.11. The productsare then coupled, as described above, with a dialkyl phosphite, toafford after side-chain deprotection and modification, as describedabove, the 21-chloro 17-(2-furoates) 300.12b and 300.13b.

Specific compounds of the invention are prepared as shown above. Thepyrazole 300.1 is reacted in tetrahydrofuran solution, with1,2-bis(bromomethyl)Cyclobutane 300.14 (J. Org. Chem., 46:3530(1981))and potassium hexamethyl disilazide, to give the alkylation products300.14 and 300.15. The 1-substituted isomer 300.15 is then reacted, inan Arbuzov reaction, with a trialkyl phosphite to yield, afterdeprotection and side-chain modification, the 21-chloro 17-(2-furoate)300.17b. The Arbuzov reaction is described in Handb. OrganophosphorusChem., 115 (1992). In this procedure, in which a bromo substituent isconverted into the corresponding phosphonate, the substrate is heated atfrom about 60° C. to about 160° C. with a five to fifty-fold molarexcess of a trialkyl phosphite, to effect the transformation.

The 2′-substituted pyrazole 300.16 is subjected to the same series ofreaction to give the amine phosphonate 300.18b.

Using the above procedures, but employing different dibromides, theproducts analogous to 300.17b and 300.18b are obtained.

EXAMPLE 301 Preparation of Representative Budesonide Derivatives

Representative compounds of the invention may be prepared as describedherein.

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in “Protective Groups in Organic Synthesis,” by T. W.Greene and P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in “OrganicReactions in Steroid Chemistry,” Vol. 1, J. Fried and J. A.

Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactive substituentsthat may be protected are shown in the accompanying schemes as, forexample, [OH], [O], etc.

For example, depicted above is a protection-deprotection sequence inwhich the 20-ketone group and/or the 21-hydroxyl group of Budesonide301.1 are protected to afford the derivative 301.2. The ketone isprotected, for example, by conversion to the cyclic ethylene ketal, byreaction in toluene solution at reflux temperature with ethylene glycoland an acid catalyst, as described in J. Am. Chem. Soc., 77:1904 (1955).Deprotection is effected by reaction with pyridinium tosylate in aqueousacetone, as described in J. Chem. Soc., Chem. Comm., 1351 (1987).

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 301.1 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 50:102 (1970). The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 101:5841 (1979).

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 301.1 is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc., Chem. Comm., 406(1983), to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The 21-hydroxyl group is protected, for example, by conversion to theacetate ester, by reaction with one molar equivalent of acetyl chloridein dichloromethane/pyridine. The 21-acetoxy group is removed by reactionwith one molar equivalent of lithium hydroxide in aqueousdimethoxyethane.

Alternatively, the 21-hydroxyl group is protected by conversion to thetert.butyl dimethylsilyl ether, by reaction in dimethylformamidesolution with one molar equivalent of tert.butylchlorodimethylsilane andimidazole, as described in J. Am. Chem. Soc., 94:6190 (1972). The silylether is removed by reaction with tetrabutylammonium fluoride intetrahydrofuran solution, as described in J. Am. Chem. Soc., 94:6190(1972).

The protected compound 301.2 is then converted into thephosphonate-containing analog 301.3, using the procedures describedbelow, and the protecting group or groups are then removed, as describedabove, to give the phosphonate 301.4.

EXAMPLE 302 Preparation of Representative Budesonide Derivatives

Depicted above is the preparation of compounds of the invention in whichthe phosphonate is attached by means of an imino or iminoxy group and avariable carbon chain. In this procedure, the ketone-protectedderivative 302.1 is reacted with an amine or hydroxylamine 302.2, inwhich R² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group,optionally incorporating a heteroatom O, S or N, or a functional groupsuch as an amide, ester, oxime, sulfoxide or sulfone, etc., or anoptionally substituted aryl, heteroaryl or aralkyl group, optionallyincorporating a heteroatom O, S or N, and X is either a phosphonategroup or a group that is subsequently converted into aphosphonate-containing substituent.

For example, X may be dialkylphosphono, bromo, hydroxy, amino, carboxyand the like. The reaction is conducted between equimolar amounts of thereactants in an aprotic solvent such as pyridine or xylene, or in analcoholic solvent such as ethanol, optionally in the presence of an acidcatalyst, to give the imine or oxime 302.3. The preparation of oximes ofsteroidal 3-ketones is described in Anal. Bioch., 86:133 (1978) and inJ. Mass. Spectrom., 30: 497 (1995). The protecting group is thenremoved, as described in Example 301, to afford the 20-keto phosphonateproduct 302.4.

Also illustrated above is the preparation of hydroxylamine ethersincorporating a phosphonate group. In this procedure, a phosphonate302.5, in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 302.6(Aldrich) to produce the ether 302.7. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for example,by treatment with trifluoroacetic acid, then gives the hydroxylamineether 302.8. The above procedure is also employed for the preparation ofsubstituted hydroxylamines which are precursors to phosphonates.

The synthesis of specific compounds of the invention is shown above. Thepreparation of compounds of the invention in which the phosphonate isattached by means of an iminoxy group is illustrated. In this procedure,the substrate 302.1, in which the 20-ketone is protected as the dimethylhydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine 302.8a, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 27:1477 (1986)and BOC-hydroxylamine, to afford the oxime 302.10. Deprotection, asdescribed in Example 301, then affords the 20-keto phosphonate 302.11.The oxime forming reaction is performed at ambient temperature inethanol-acetic acid solution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 302.8a, different oxime ethers 302.2, the corresponding products302.4 are obtained.

The synthesis of specific compounds of the invention is shown above. Thepreparation of compounds of the invention in which the phosphonate groupis attached by means of a benzyloxy oxime group is illustrated. In thisprocedure, the dienone 302.1, in which the 20-ketone is protected as thedimethyl hydrazone, is reacted, as described above, withO-(2-bromobenzyl)hydroxylamine 302.9, prepared as described above from2-bromobenzyl bromide and BOC-protected hydroxylamine 302.6, to give theoxime 302.12. The protecting group is then removed to yield the 20-ketoproduct 302.13. The latter product is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite 302.14 to afford thephosphonate 302.15. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 35:1371 (1992). The reaction is performed atca. 100° in an inert solvent such as toluene, in the presence of a basesuch as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 302.13 is coupled with a dialkylvinylphosphonate 302.16 (Aldrich) to afford the phosphonate 302.17. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in “Advanced Organic Chemistry,” by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res.,12:146 (1979). The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 302.17 isreduced, for example, by reaction with diimide, to produce the saturatedanalog 302.18. The reduction of olefinic bonds is described in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromobenzylreagent 302.9, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 302.15, 302.17 and 302.18 areobtained.

The preparation of specific compounds of the invention is shown above.The preparation of compounds of the invention in which the phosphonateis attached by means of a 4-phenylimino group is illustrated. In thisprocedure, the substrate 302.1, in which the 20-ketone is protected asthe dimethylhydrazone, is reacted with a dialkyl 4-aminophenylphosphonate 302.20 (Epsilon), to give, after deprotection, the imineproduct 302.21. The imine forming reaction is conducted in a hydrocarbonsolvent such as toluene or xylene, at reflux temperature, in thepresence of a basic catalyst such as sodium methoxide, or an acidcatalyst such as p-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the 4-aminophenylphosphonate 302.20 different amino-substituted aryl or heteroarylphosphonates, products analogous to 302.21 are obtained.

The preparation of specific compounds of the invention is shown above.The preparation of compounds of the invention in which the phosphonateis attached by means of an oximino group and a carbamate linkage isillustrated. In this procedure, the dienone 302.1, in which the20-ketone is protected as the dimethylhydrazone, is reacted with4-aminobutyl hydroxylamine 302.22 (Pol. J. Chem., 55:1163 (1981)) toyield the oxime 302.23. The reaction of steroidal 1,4-dien-3-ones withhydroxylamines is described in J. Steroid Bioch., 7: 795 (1976). Thereaction is performed between equimolar amounts of the reactants in apolar organic solvent such as pyridine or methanol, optionally in thepresence of acetic acid or sodium acetate. The product 302.23 is thencoupled with a dialkyl 2-hydroxyethyl phosphonate 302.24 (Epsilon) andcarbonyl diimidazole, to yield, after deprotection, the carbamate oxime302.25. The preparation of carbamates is described in “ComprehensiveOrganic Functional Group Transformations,” A. R. Katritzky, ed.,Pergamon, 1995, Vol. 6, p 416ff, and in “Organic Functional GroupPreparations,” by S. R. Sandler and W. Karo, Academic Press, 1986, p.260ff. In the procedure, the amine is reacted in an inert aproticsolvent such as dichloromethane or tetrahydrofuran, with phosgene or afunctional equivalent thereof, such as carbonyl diimidazole,triphosgene, pentafluorophenyl carbonate and the like, to afford thecorresponding activated acylamine. The latter compound is then reactedwith an alcohol to yield the carbamate.

Using the above procedures, but employing, in place of theamino-substituted hydrazine 302.22, different amino-substitutedhydrazines, and/or different hydroxy-substituted phosphonates, theproducts analogous to 302.25 are obtained.

EXAMPLE 303 Preparation of Representative Budesonide Derivatives

The preparation of the phosphonate esters of the invention in which thephosphonate group is attached to the 1′ or 2′ position of the pyrazolering, by means of an aromatic or heteroaromatic group, a heteroatomand/or a variable carbon chain is shown above.

In this procedure, the dienone 301.2, in which the 21-hydroxyl group isprotected as described in Example 301 is reduced to afford the1,2-dihydro product 303.1. The catalytic hydrogenation reaction iseffected by the use of tris(triphenylphosphine)rhodium (I) chloride, forexample as described in J. Med. Chem., 2001, 44, 602. The product isthen reacted with ethyl formate and a base such as sodium hydride, in aninert solvent such as toluene or dimethylformamide, as described in J.Am. Chem. Soc., 1964, 86, 1520, to afford the 2-formyl product 303.2.This compound is then reacted with an alkyl, aralkyl, aryl or heteroarylhydrazine 303.3, in which the substituent X is either a phosphonategroup or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X may bedialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. Thereaction yields, after deprotection of the 21-hydroxyl group, theisomeric 2′- and 1′-aryl pyrazoles 303.4 and 303.5. The pyrazole-formingreaction is performed between equimolar amounts of the reactants in anacidic solvent such as acetic acid, as described in J. Am. Chem. Soc.,1964, 86, 1520. The pyrazoles 303.4 and 303.5 are then transformed, forexample by the procedures described herein, into the phosphonates 303.6and 303.7.

The preparation of specific compounds of the invention is illustratedabove. The preparation of phosphonates of the invention in which thephosphonate is attached by means of a phenyl ring or a stilbene moietyis shown. In this procedure, the ketoaldehyde 303.2 is reacted, asdescribed above, with 4-bromophenyl hydrazine 303.8 (J. Organomet.Chem., 1999, 62, 581) to give the pyrazoles 303.9 and 303.10. The2′-substituted isomer 303.9 is then reacted, as described above, with adialkyl phosphite 303.11 to give the phosphonate 303.12.

The isomeric pyrazole 303.10 is reacted in a Heck reaction, as describedabove, with one molar equivalent of a dialkyl 4-vinylphenyl phosphonate303.13 (Macromolecules, 1998, 31, 2918) to yield the phosphonate 303.14.

Using the above procedures, but employing different bromo-substitutedhydrazines, and/or different alkenyl-substituted phosphonates, theproducts analogous to 303.12 and 303.14 are obtained.

The synthesis of specific compounds of the invention is shown above. Thepreparation of the phosphonates of the invention in which thephosphonate group is attached by means of an alkoxy or alkylthio groupand an aromatic ring is illustrated. In this procedure, the ketoaldehyde303.2 is reacted, as described above, with 4-hydroxyphenyl hydrazine303.15 (EP 437105) to produce the pyrazoles 303.16 and 303.17. The2′-substituted isomer 303.16 is then reacted in dimethylformamidesolution at 70° with one molar equivalent of a dialkyl bromopropylphosphonate 303.18 (J. Amer. Chem. Soc., 2000, 122, 1554) and cesiumcarbonate, to give the ether phosphonate 303.19.

Alternatively, the 1′-substituted pyrazole 303.22 is coupled in aMitsonobu reaction, with a dialkyl 2-mercaptoethyl phosphonate 303.20(Zh. Obschei. Khim., 1973, 43, 2364) to prepare the thioetherphosphonate 303.21. The preparation of aromatic ethers and thioethers bymeans of the Mitsonobu reaction is described, for example, inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.448, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335. Thephenol and the alcohol or thiol component are reacted together in anaprotic solvent such as, for example, tetrahydrofuran, in the presenceof a dialkyl azodicarboxylate and a triarylphosphine, to afford theether or thioether products. The procedure is also described in Org.React., 1992, 42, 335-656.

Using the above procedures, but employing, in place of the hydroxyphenylhydrazine 303.15, different hydroxyaryl hydrazines, and/or differentdialkyl bromo- or mercapto-substituted phosphonates, the productsanalogous to the compounds 303.19 and 303.21 are obtained.

EXAMPLE 304 Preparation of Representative Budesonide Derivatives

The preparation of the phosphonate esters of the invention in which thephosphonate group is attached by means of a variable carbon linkage isshown above. In this procedure, the ketoaldehyde 303.2 is reacted withhydrazine to afford the pyrazole derivative 304.1. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 304.2, in which R² and X are as defined above, or a reactivebromoheteroaromatic reagent, to yield the alkylation products 304.3 and304.4. The alkylation of substituted pyrazoles is described, forexample, in Heterocyclic Chemistry, by T. L. Gilchrist, Longman, 1992,p. 309. The reaction is performed between equimolar amounts of thesubstrates in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 304.3 and 304.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 304.5 and 304.6, usingthe procedures described herein.

The preparation of specific compounds of the invention is shown above.The pyrazole 304.1 is reacted in dimethylformamide solution at 70° withone molar equivalent of a dialkyl 4-bromomethylphenyl phosphonate 304.7(Tet., 1998, 54, 9341) and lithium hexamethyl disilazide, to give thepyrazoles 304.8 and 304.9. Using the above procedures, but employingdifferent bromomethyl-substituted phosphonates, the products analogousto 304.8 and 304.9 are obtained.

The preparation of specific compounds of the invention is shown above.The pyrazole 304.1 is reacted in tetrahydrofuran solution with1,3-bis(bromomethyl)Cyclopentane 304.10 (Bull. Soc. Chim. FR., 1975,1295) and sodium hydride, to give the alkylation products 304.11 and304.12. The 2′-substituted isomer 304.11 is then reacted, in a Arbuzovreaction, with a trialkyl phosphite to yield the phosphonate 304.13. TheArbuzov reaction is described in Handb. Organophosphorus Chem., 1992,115. In this procedure, in which a bromo substituent is converted intothe corresponding phosphonate, the substrate is heated at from about 60°to about 160° with a five to fifty-fold molar excess of a trialkylphosphite, to effect the transformation.

The 2′-substituted pyrazole 304.12 is reacted at 70° indimethylformamide solution with one molar equivalent of a dialkylmethylaminomethyl phosphonate 304.14 (AsInEx) and cesium carbonate, togive the amine phosphonate 304.15.

Using the above procedures, but employing different dihalides, and/ordifferent amino-substituted phosphonates, the products analogous to304.13 and 304.15 are obtained.

EXAMPLE 305 Preparation of Representative Cyclosporin A Derivatives

In general, phosphonate interconversions of the compounds of theinvention, as described in Examples 305-308, can be performed asdescribed herein. The final compounds are synthesized according to themethods described herein. Exemplary intermediate phosphonate esters,e.g., 305.1, 305.2, 305.3 and 305.3a, are shown below and thesecompounds can be used to prepare final compounds, such as thoseillustrated below, by one skilled in the art, using known methods forsynthesis of substituted phosphonates. These methods are similar tothose described for the synthesis of amides. The preparation of amidesfrom carboxylic acids and derivatives is described, for example, in“Organic Functional Group Preparations,” by S. R. Sandler and W. Karo,Academic Press, 1968, p. 274. Further methods are described below forthe synthesis of the phosphonate diesters and can in some cases beapplied to the synthesis of phosphor-amides.

In the following schemes, the conversion of various substituents intothe group link-P(O)(^(OR) ¹)₂, where R¹ is defined as above, or indeedthe final stage of P(O)RR^(o), as defined above, can be effected at anyconvenient stage of the synthetic sequence, or in the final step. Theselection of an appropriate step for the introduction of the phosphonatesubstituent is made after consideration of the chemical proceduresrequired, and the stability of the substrates to those procedures. Itmay be necessary to protect reactive groups, for example hydroxyl,amino, during the introduction of the group link-P(O)(^(OR) ¹)₂ orP(O)RR^(o)

In the succeeding examples, the nature of the phosphonate ester groupP(O)(^(OR) ¹)₂ can be varied, either before or after incorporation intothe scaffold, by means of chemical transformations. The transformations,and the methods by which they are accomplished, are described below.

Protection of Reactive Substituents

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in “Protective Groups in Organic Synthesis,” by T. W.Greene and P. G. M Wuts, Wiley, Third Edition 1999. Reactivesubstituents, which may be protected, are shown below as, for example,[OH], [SH], etc.

Preparation of Intermediate Phosphonates

The intermediate phosphonate esters 305.1-305.3a involved in conversioninto the prodrug phosphonate moieties bearing amino acid, or lactateesters are shown above. Cyclosporin A (CsA) can be purchased from SigmaAldrich, synthesized (see U.S. Pat. No. 4,396,542) or obtained frombiological sources as described in U.S. Pat. No. 4,117,118. Othercyclosporin derivatives can be either synthetic in nature (see U.S. Pat.No. 4,396,542) or isolated by similar means to CsA (see U.S. Pat. No.6,410,696 B1).

EXAMPLE 306 Preparation of Representative Cyclosporin A Derivatives

The preparation of the phosphonate linkage to CsA through the hydroxylgroup of amino acid 1 to give compounds of the invention is shown above.CsA 306.1 is dissolved in a suitable solvent such as, for example, DMFor other non-protic solvent, and is then treated with the phosphonatereagent 306.2, bearing a leaving group, for example, bromine, mesyl,tosyl, or trifluoromethanesulfonyl in the presence of a suitable organicor inorganic base. For example, 306.1 dissolved in DMF, is treated withone equivalent of sodium hydride and one equivalent of(toluene-4-sulfonylmethyl)-phosphonic acid dibenzyl ester 306.3,prepared according to the procedures in JOC 1996, 61,22, p7697, to giveCsA phosphonate 306.4. Using the above procedure but employing differentphosphonate reagents 306.2 in place of 306.3 there are obtained thecorresponding products of the invention bearing different linkinggroups.

EXAMPLE 307 Preparation of Representative Cyclosporin A Derivatives

The preparation of CsA—phosphonate conjugates of the invention isillustrated above. The hydroxyl group of amino acid 1 is first protectedwith a suitable protecting group, for example silyl ethers, benzylethers, trityl ethers etc as described in Greene and Wuts, “ProtectingGroups in Organic Synthesis,” 3^(rd) Edition, John Wiley and Sons. Theprotected product 307.2 is then treated with an oxidizing agent, manyexamples of which are described in Comprehensive OrganicTransformations, John Wiley & Sons, 2^(nd) Ed, R. C. Larock, p 1211-1215to give the aldehyde. Aldehyde 307.3 is then treated with a aminephosphonic acid ester of the general formula 307.4 under reductiveamination conditions to afford amine 307.5. The preparation of amines bymeans of reductive amination procedures is described, for example, in“Comprehensive Organic Transformations,” by R. C. Larock, 2^(nd)edition, p. 835. In this procedure, the amine component and the aldehydecomponent are reacted together in the presence of a reducing agent suchas, for example, borane, sodium cyanoborohydride or diisobutylaluminumhydride, to yield the amine product. Finally, deprotection of thehydroxyl group following procedures documented in Greene and Wuts,“Protecting Groups in Organic Synthesis,” 3^(rd) Edition, John Wiley andSons, p 116-121 gives the phosphonate.

For example, 307.1 is treated in pyridine and dichloromethane withtrimethylsilyl chloride, as described in U.S. Pat. No. 6,410,696 B1, togive silyl ether 307.5. Silyl ether 307.5 is then treated with ozonefollowed by work up with dimethyl sulfide to give aldehyde 307.8.Aldehyde 307.8 is treated with one equivalent of the hydrochloride saltof (2-amino-ethyl)-phosphonic acid ester diethyl ester 307.9, preparedaccording to J. Med. Chem. 1998, 41, 23, p 4439, and a suitable base,e.g., hunigs base, triethylamine, or the likes, until the imine isformed. The intermediate imine solution is then treated with sodiumcyanoborohydride to give the amine 307.10. Amine 307.10 is thendeprotected by treatment with TBAF in an aprotic solvent such as THF ordioxane to give phosphonate 307.11. Using the above procedure butemploying different phosphonate reagents 307.4 in place of 307.9 thereare obtained the corresponding products bearing different linkinggroups.

EXAMPLE 308 Preparation of Representative Cyclosporin A Derivatives

The preparation of CsA phosphonate conjugates of the invention wherebythe phosphonate is linked onto the alanine nitrogen in amino acids 7 and8 is shown above. Protected CsA 307.2 (Example 307) is first treatedwith a base, sufficiently basic to remove the amide proton, for example,metal hydrides, metal amides. The product is then treated with aphosphonate reagent 306.2 bearing a leaving group such as, for example,bromine, mesyl, tosyl, or trifluoromethanesulfonyl phosphonates, to give308.1 and 308.2. The alkylated products are then separated bychromatography and independently deprotected using conventionalconditions described in Greene and Wuts, Protecting groups in OrganicSynthesis, 3^(rd) Edition, John Wiley and Sons inc. p 116-121 to givecompounds of the invention. For example, silyl ether 307.5, in tolueneis treated with sodium hydride and 15-crown-5-ether followed by oneequivalent of bromomethyl phosphonic acid diallyl ester, 308.3(Lancaster), to give phosphonates 308.4 and 308.5, respectively.Phosphonates 308.4 and 308.5 are then deprotected by treatment with TBAFin an aprotic solvent such as THF or dioxane to give 308.6 and 308.7,respectively, in which the linkage is a methylene group. Using the aboveprocedure, but employing different phosphonate reagents 306.2 in placeof 308.3, there are obtained the corresponding products with differentlinking groups.

EXAMPLE 309 Preparation of Representative Mizoribine Derivatives

Representative compounds of the invention may be prepared according tothe following methods.

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis (Second Edition, Wiley, 1991). The protection anddeprotection of steroidal ketones is described in J. Fried and J. A.Edwards, Organic Reactions in Steroid Chemistry, Vol. 1 375ff (vanNostrand Reinhold, 1972). Reactive substituents which may be protectedare shown in the accompanying schemes as, for example, [OH], [O], etc.

Depicted above is the preparation of phosphonates of the invention. The5-hydroxy-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide 309.1 (preparedaccording to U.S. Pat. No. 3,888,843) can be treated in a solvent suchas tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 1986, 27, 1477) is added, yielding thedesired phosphonate diester 309.2, e.g., 309.3.

EXAMPLE 310 Preparation of Representative Compounds of Mizoribine

The preparation of the phosphonate esters of the invention is depictedabove. Compound 310.1,5-hydroxy-1-(4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-ylmethyl)-1H-imidazole-4-carboxylicacid amide can be prepared by addition of the imidazole base (J P Kokai76 88965) onto the 3,5-bis-protected 2-deoxy-D-erythro-pentofuranosylchloride (Hayashi, M. et al., Chem. Pharm. Bull., 1975, 23, 1, 245;Montgomery, J. A. et al., J. Med. Chem., 1969, 12, 3, 498; and Iwamoto,R. H. et al., J. Med. Chem., 1963, 6, 684). Compound 310.1 is thenprotected on the imidazol-4-ol. Oxidation of the 5′-OH followed byelimination provides glycal 310.3 (see the procedure of Zemlicka J. etal., J. Am. Chem. Soc., 1972, 94, 9, 3213). Selenoetherificationprovides the protected phosphonate 310.4 (Kim, C. et al., J. Org. Chem.,1991, 56, 2642). Oxidative elimination of the phenylselenide (asdescribed in Kim, C. et al., J. Org. Chem., 1991, 56, 2642) followed bystereoselective dihydroxylation provides the diol 310.6. Finally, theprotecting group is removed to provide 310.7.

Illustrated above is the preparation of specific compounds of theinvention. Specifically, compound 310.1,5-hydroxy-1-(4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-ylmethyl)-1H-imidazole-4-carboxylicacid amide, which can be prepared by addition of the imidazole base (J PKokai 76 88965; also Schipper, E. et al., J. Am. Chem. Soc., 1952, 74,350) onto the 3,5-bis-protected 2-deoxy-D-erythro-pentofuranosylchloride (Hayashi, M. et al., Chem. Pharm. Bull., 1975, 23, 1, 245;Montgomery, J. A. et al., J. Med. Chem., 1969, 12, 3, 498; and Iwamoto,R. H. et al., J. Med. Chem., 1963, 6, 684) is first protected using aTBS group. Subsequent oxidation with PtO₂ proceeds to provide carboxylicacid 310.2. Decarboxylative elimination is achieved usingdimethylformamide dineopentyl acetal in DMF at high temperature(Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9, 3213). Once thefuranoid glycal 310.8 is in hand, it is treated with silver perchloratein the presence of diethyl(hydroxylmethyl)phosphonate (Phillion, D. etal., Tetrahedron Lett., 1986, 27, 1477) to provide the phosphonate 310.9(Kim, C. et al., J. Org. Chem., 1991, 56, 2642). Oxidative eliminationof the selenide followed by dihydroxylation using osmium tetraoxideprovides a diol with the desired stereochemistry. Deprotection of theTBS group can be achieved using TBAF.

EXAMPLE 311 Preparation of Representative BCX-1777 Derivatives

In general, the preparation of the following representative compounds ofthe invention is illustrated below.

Compounds of the invention such as 311.5 can be made according to thegeneral route outlined below.

A specific compound of the invention may be prepared as follows:

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound311.6, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOCanhydride as described in Greene, T., Protective groups in organicsynthesis, Wiley-Interscience, 1999. Compound 311.6 is then treated in asolvent such as tetrahydrofuran or dimethylformamide with a base such assodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added,yielding the desired phosphonate 311.6 after deprotection of the BOCgroup using trifluoroacetic acid (TFA).

EXAMPLE 312 Preparation of Representative BCX-1777 Derivatives

The preparation of representative compounds of the invention are shownbelow. Compounds such as 312.2 and 312.3 can be made according to thegeneral route outlined below.

A specific compound of the invention can be prepared as follows:

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound312.4, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOCanhydride as described in Greene, T., “Protective Groups in OrganicSynthesis,” Wiley-Interscience, 1999. Subsequent protection of theprimary alcohol using a TBS group can be achieved using TBSCl andimidazole in solvents such as CH₂Cl₂ as described in Greene, T.“Protective Groups in Organic Synthesis,” Wiley-Interscience, 1999 toprovide compound 312.1. Compound 312.1 is then treated in a solvent suchas tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 1986, 27, 1477) is added, yielding amixture of the desired phosphonate diester 312.2 and 312.3 afterdeprotection of the BOC group using trifluoroacetic acid (TFA).Compounds 312.2 and 312.3 can be also prepared via a more complicated 2′OH protected analog of 312.1 followed by alkylation using the diethylphosphonomethyltriflate to provide compound 312.2 exclusively. Compound312.3 can also be prepared by installation of a different protectinggroup at the 3′ OH position, followed by deprotection of 2′ OH andalkylation with diethyl phosphonomethyltriflate at the 2′ centerfollowed by global deprotection.

EXAMPLE 313 Preparation of Representative Zileuton Compounds of theInvention

Specific compounds of the invention can be prepared as follows:

Diethyl(trifluromethanesulfonyloxy)methylphosphonate

To a solution of diethyl hydroxymethylphosphonate (14.0 g, 83.27 mmol)and 2,6-lutidine (10.7 g, 99.9 mmol) in DCM (80 mL) at −78° C. was addedtriflic anhydride (25.83 g, 91.5 mmol), dropwise, and the solution wasstirred for 15 minutes. The resulting mixture was then warmed to 0° C.,stirred for 30 minutes, and diluted with ethyl acetate. The mixture wassequentially washed with 1N HCl, saturated NaHCO₃, and brine and thenconcentrated. The residue was purified by silica column chromatography(3:2 hexane/ethylacetate), affording the desired product as a clearyellowish oil. Yield (18.8 g, 75%)

MS m/z (MH)⁺ 301.

(4-Acetyl-phenoxymethyl)-phosphonic acid diethyl ester

A reaction mixture of 4-hydroxyacetophenone (1.58 g, 11.10 mmol),trifluromethanesulfonic anhydride (3.66 g, 12.2 mmol) and cesiumcarbonate (4.34 g, 13.32 mmol) in DMF (55 mL) was stirred overnight atroom temperature. The reaction mixture was diluted with water (100 mL)and the product was extracted with ethyl acetate (2×100 mL), washed withwater and brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith ethyl acetate/hexane (2:3), to yield the product (4.6 g, 78%).

MS m/z (MH)⁺ 287.Preparation of Oxime (313.20)

A mixture of 313.14 (1.5 g, 5.24 mmol), hydroxylamine hydrochloride(0.437 g, 6.28 mmol), pyridine (15 mL) and ethanol (15 mL) was stirredat room temperature for two days. The reaction mixture was concentratedto dryness, taken up in ether (20 mL) and washed with 3N HCl. Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo. The resulting solid was purified chromatography on silica gel,eluting with CHCl₃:MeOH (98:2), to yield the desired product (1.1 g,68%).

MS m/z (MH)⁺ 301.Reduction of Oxime (313.22)

Oxime (313.20) (0.3 g, 1 mmol) was dissolved in ethanol (10 mL) andfreshly-prepared BH₃-Py complex (1 mL) was added. The solution wasstirred for 10 minutes at room temperature, whereupon 6 N HCl (1.8 mL)was added, dropwise. Further stirring was continued for 1 hour at roomtemperature. The reaction mixture was then brought to pH 8-9 by additionof 2N NaOH. The product was extracted with ethyl acetate (2×50 mL),dried over anhydrous sodium sulfate and concentrated to yield a viscousliquid (0.32 g) which contained some residual pyridine but was suitablefor use in the next step.

MS m/z (MH)⁺ 303.Synthesis of N-Hydroxy Urea (313.24)

To a solution of 313.22 (0.3 g, 1 mmol) in 1,4-dioxane (5 mL) and THF (5mL) was added trimethylsilyl isocyanate (0.16 mL, 1.2 mmol). Thereaction mixture was heated at 90° C. for 1 h, cooled to roomtemperature and poured into a ice-cooled saturated solution of ammoniumchloride. The product was extracted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withCHCl₃-MeOH, (96:4) to give the desired product (0.14 g, 40%). MS m/z(MH)⁺ 347. ¹H NMR (CDCl₃) δ 1.32-1.37 (m, 6H, CH₃) 1.48-1.51 (d, 3H,CH₃, 4.13-4.23 (m, 6H, —CH₂, —CH₂, OCH₂—P) 5.3-5.4(m,3H, —CH—, NH₂),6.86-7.35 (m, 4H, C₆H₄), 8.29 (1H, N—OH). HPLC Purity 79% major 16%minor (sphereclone 5 μL, H₂O: MeCN, 20 minute linear gradient from10-90% MeCN, 1.0 mL/min). ³¹P NMR (CDCL₃) δ 19.75-20.17, m.

Specific compounds of the invention can be prepared as follows:

Preparation of 313.16

A reaction mixture of 3-hydroxyacetophenone (1.00 g, 7.32 mmol)trifluromethanesulfonic anhydride (2.46 g, 8.05 mmol) and cesiumcarbonate (2.86 g, 8.79 mmol) in DMF (50 mL) was stirred overnight atroom temperature. The reaction mixture was diluted with water (100 mL)and the product was extracted with ethyl acetate (2×100 mL), washed withwater and brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith ethyl acetate/hexane (2:3), to yield the product (1.5 g, 72%yield).

MS m/z (MH)+287.Preparation of Oxime 313.21

A mixture of 313.16 (0.5 g, 1.75 mmol), hydroxylamine hydrochloride(0.145 g, 2.09 mmol), pyridine (10 mL) and ethanol (10 mL) was stirredat room temperature for two days. The reaction mixture was concentratedto dryness, taken up in ether (20 mL) and washed with 3N HCl. Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo. The resulting solid was purified chromatography on silica gel,eluting with CHCl₃:MeOH (98:2), to yield the desired product (0.3 g,61%).

MS m/z (MH)⁺ 301.Reduction of Oxime 313.25

Oxime (313.21) (0.304 g, 1 mmol) was dissolved in ethanol (10 mL) andfreshly-prepared BH₃-Py complex (1 mL) was added. The solution wasstirred for 10 minutes at room temperature, whereupon 6 N HCl (1.8 mL)was added, dropwise. Further stirring was continued for 1 hour at roomtemperature. The reaction mixture was then brought to pH 8-9 by additionof 2N NaOH. The product was extracted with ethyl acetate (2×50 mL),dried over anhydrous sodium sulfate and concentrated to yield a viscousliquid (0.32 g) which contained some residual pyridine but was suitablefor use in the next step.

MS m/z (MH)⁺ 304.Synthesis of N-Hydroxy Urea (313.26)

To a solution of 313.21 (0.3 g, 1 mmol) in 1,4-dioxane (5 mL) and THF (5mL) was added trimethylsilyl isocyanate (0.16 mL, 1.2 mmol). Thereaction mixture was heated at 90° C. for 1 hour, cooled to roomtemperature and poured into a ice-cooled saturated solution of ammoniumchloride. The product was extracted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by chromatography on silica gel, eluting withCHCl₃-MeOH, (96:4) to give the desired product (0.14 g, 40%). MS m/z(MH)⁺ 347. ¹H NMR (CDCl₃) δ 1.30-1.38 (m, 6H, 2-CH₃) 1.52-1.55(d, 3H,CH₃, 4.1-4.37(m, 6H, —CH₂, —CH₂, OCH₂—P) 5.27-5.49(m,3H, —CH—, NH₂)6.81-7.27 (m, 4H, C₆H₄)8.13 (1H, N—OH). HPLC Purity 82% (sphereclone 5μL H₂O: MeCN, 20 minute linear gradient from 10-90% MeCN, 1.0 mL/min).³¹P NMR (CD₃OD) δ 21.69-22.12, m.

EXAMPLE 314 Preparation of Representative Zardaverine Compounds of theInvention

Specific compounds of the invention can be prepared as follows:

Preparation of 314.2.

A mixture of 50 mg Zardaverine (0.186 mmol), 120 mg 1,4-dibromo-2-butene(0.56 mmol), 10.5 mg (0.187 mmol) KOH and 6.5 mg (0.02 mmol) TBAB in 1mL benzene was stirred vigorously for 6 hrs. The suspension became twophases with a clear organic upper layer. TLC indicated the totalconsumption of the starting material and the formation of one newcompound. The mixture was mounted directly on a silica gel column (1:1hexanes/ethyl acetate) and 65 mg of the title compound was isolated as awhite solid (87% yield). ESI-MS m/z 401 (MH)⁺. IR 1666 (C═O) cm⁻1.

Preparation of 314.4

A solution of 65 mg 314.2 (0.125 mmol) and 0.22 mL (1.25 mmol) triethylphosphite in 1 mL toluene was heated at reflux for 2 hrs. TLC indicatedthe total consumption of the starting material and the formation of onenew compound. The mixture was mounted directly on a silica gel column(2% MeOH in ethyl acetate) and 65 mg of the title compound was isolatedas a clear liquid (87% yield).

HPLC purity 100% (Sphereclone 5 μL, H₂O: MeCN, 20 min linear gradientfrom 10-90% MeCN, 1.0 mL/min). ESI-MS m/z 459 (MH)⁺. ¹H NMR (300 MHz,CDCl₃) δ 7.65 (d, J=9.6 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.29-7.21 (m,2H), 7.03 (d, J=9.6 Hz, 1H), 6.61 (t, J=74.8 Hz, 1H), 5.98-5.72 (m, 2H),4.84 (t, J=5.2 Hz, 2H), 4.07 (quintet, J=7.2 Hz, 4H), 3.97 (s, 3H), 2.62(dd, J=21.4, 6.5 Hz, 2H), 1.26 (t, J=7.0 Hz, 6H). ³¹P NMR (120 MHz,CDCl₃) δ 27.14 (m).

Preparation of 314.6

A mixture of 50 mg Zardaverine (0.186 mmol), 120 mg m-xylylene dibromide(0.56 mmol), 10.5 mg (0.187 mmol) KOH and 6.5 mg (0.02 mmol) TBAB in 1mL benzene was stirred vigorously for 7.5 hrs. The suspension became twophases with a clear organic upper layer. TLC indicated the totalconsumption of the starting material and the formation of one newcompound. The mixture was mounted directly on a silica gel column (1:1hexanes/ethyl acetate) and 64 mg of the title compound was isolated as awhite solid (77% yield). ESI-MS m/z 451 (MH)⁺.

Preparation of 314.10

A solution of 64 mg 314.6 (0.142 mmol) and 0.22 mL (1.25 mmol) triethylphosphite in 1 mL toluene was heated to reflux for 2 hrs. TLC indicatedthe total consumption of the starting material and the formation of onenew compound. The mixture was mounted directly on a silica gel column(2% MeOH in ethyl acetate) and 70 mg of the title compound was isolatedas a white solid (97% yield). HPLC purity >98% (Sphereclone 5 μL, H₂O:MeCN, 20 min linear gradient from 10-90% MeCN, 1.0 mL/min). ESI-MS m/z509 (MH)⁺. ¹H NMR (300 MHz, CDCl₃) δ 7.64 (d, J=9.7 Hz, 1H), 7.43 (d,J=1.8 Hz, 1H), 7.4-7.20 (m, 6H), 7.02 (d, J=9.7 Hz, 1H), 6.60 (t, J=74.9Hz, 1H), 5.39 (s, 2H), 4.02-3.16 (m, 4H), 3.96 (s, 3H), 3.13 (d, J=21.6Hz, 2H), 1.18 (t, J=7.1 Hz, 6H). ³¹P NMR (120 MHz, CDCl₃) δ 26.68 (m).

Preparation of 314.7

A mixture of 38 mg Zardaverine (0.142 mmol), 128 mg methyl3-(bromomethyl)benzoate (0.56 mmol), 10.5 mg (0.187 mmol) KOH and 6.5 mg(0.02 mmol) TBAB in 1 mL benzene was stirred vigorously for 7.5 hrs. Thesuspension became two phases with a clear organic upper layer. TLCindicated the total consumption of the starting material and theformation of one new compound. The mixture was mounted directly on asilica gel column (1:1 hexanes/ethyl acetate) and 55 mg of the titlecompound was isolated as a white solid (94% yield). ESI-MS m/z 417(MH)⁺.

Preparation of 314.12

A mixture of 55 mg Zardaverine (0.132 mmol), 55 mg LiOH.H₂O (1.3 mmol),2 mL MeOH, 1 mL THF and 0.3 mL water was stirred vigorously at roomtemperature overnight. TLC indicated the total consumption of thestarting material and the formation of one new compound. The solvent wasevaporated under reduced pressure. The residue was diluted with CH₂Cl₂,acidified with 1 N HCl, and extracted with CH₂Cl₂. The organic phase wascombined, dried and concentrated to give 49 mg of white solid (92%yield), which was used without further purification. ESI-MS m/z 403(MH)⁺.

Preparation of 314.13

To a solution of 49 mg 314.12 (0.122 mmol) in 0.5 mL CH₂Cl₂ was added 76mg PyBop (0.146 mmol) at 0° C., followed by 0.063 mL (i-Pr)₂NEt (0.366mmol). The mixture was stirred at room temperature for 2 hr until TLCindicated the total consumption of the starting material. The mixturewas mounted directly on a silica gel column (45:1 ethyl acetate:methanol) and 45 mg of the title compound was isolated as a yellow solid(67% yield). HPLC purity >99% (Sphereclone 5 μL, H₂O: MeCN, 20 minlinear gradient from 10-90% MeCN, 1.0 mL/min). ESI-MS m/z 552 (MH)⁺. ¹HNMR (300 MHz, CDCl₃) δ 7.92 (s, 1H), 7.65 (d, J=9.8 Hz, 1H), 7.75-7.59(m, 2H), 7.48-7.38 (m, 2H), 7.32-7.29 (m, 2H), 7.03 (d, J=9.7 Hz, 1H),6.60 (s, br, 1H), 6.59(t, J=74.8 Hz, 1H), 5.44 (s, 2H), 4.20-4.10 (m,4H), 3.95 (s, 3H), 3.89 (dd, J=12.1, 5.8 Hz, 2H), 1.31 (t, J=7.1 Hz,6H). ³¹P NMR (120 MHz, CDCl₃) δ 23.21 (m).

Preparation of 314.15

To 30 mg 314.10 (0.066 mmol) in 1.7 mL acetonitrile was added 0.3 mLTMSBr at 0° C., and the solution was stirred at room temperatureovernight. TLC indicated the total consumption of the starting material.The mixture was cooled to 0° C. before 1 mL MeOH was added, and themixture was stirred at room temperature for 30 min. The solvent was thenremoved under vacuum. A sample of 5 mg of the red residue (total 30 mg)was cooled to 0° C., 0.5 mL and 1 N NaOH was added, followed by 0.5 mLwater. The mixture was stirred vigorously and then extracted with 1 mLether 3 times. The aqueous phase was acidified to ca. pH 1 withconcentrated HCl. and extracted with 2 mL portions of EtOAc 5 times. Thecombined EtOAc extracts were concentrated to furnish 3 mg of the titlecompound as a yellow solid (68% yield). HPLC purity >95% (Sphereclone 5μL, H₂O: MeCN, 20 min linear gradient from 10-90% MeCN, 1.0 mL/min).ESI-MS m/z 453 (MH)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.09 (d, J=9.0 Hz,1H), 7.59-6.87 (m, 9H), 5.31 (s, 2H), 3.90 (s, 3H), 2.96 (d, J=22.1 Hz,2H).

EXAMPLE 315 Preparation of Representative Indomethacin Compounds of theInvention.

Specific compounds of the invention can be prepared as follows.

Synthesis of 315.19

Step 1: Indomethacin (500 mg, 1.40 mmol) was dissolved in dry benzene (5mL) under an argon atmosphere, and oxalyl chloride (183 μL, 2.10 mmol)was added, followed by 1 drop of dry DMF. The reaction mixture wasstirred at room temperature for 24 hrs and concentrated to dryness. Theresidue was co-evaporated with dry benzene (5 mL) to remove traces ofoxalyl chloride. The solid obtained (556 mg) was dried under vacuum for4 hrs at room temperature and carried over to next step withoutpurification.

Step 2: Diethyl(aminomethyl)phosphonate oxalate (381 mg, 1.48 mmol) wasdissolved in 5 mL of dry DMF under argon atmosphere. Triethylamine (413μL, 2.96 mmol) was added, and the reaction mixture was stirred for 15min at room temperature. The crude acid chloride (556 mg, 1.48 mmol) asa solution in 3 mL of dry DMF was added dropwise to the reactionmixture. After completion of the addition the reaction was stirred for24 hrs at room temperature. TLC (CHCl₃:MeOH, 95:5) showed completeconsumption of starting material. Deionized water (10 mL) was added andthe mixture was extarcted with ethylacetate (2×15 mL). The ethyl acetateextracts were combined and washed with 1N HCl (5 mL) followed bydeionized water (10 mL), and dried over Na₂SO₄. Concentration gave asyrup that on purification by preparative-TLC (4 plates, 20×20 cm, 2000microns, solvent: CHCl₃:MeOH, 95:5) gave gummy solid. The gummy solidwas crystallized from diethyl ether (3 mL) to give a solid (294 mg, 42%yield). HPLC: 99.5% pure (Sphereclone 5 μL, H₂O:MeCN, 20 min linear from10-90% MeCN, 1.0 mL/min). ESI-MS m/z 507 [M+H]⁺. ¹H NMR (300 MHz,CDCl₃): δ 7.71-7.67 (2H, m, ArH), 7.51-7.48 (2H, m, ArH), 6.91-6.86 (2H,m, ArH), 6.72-6.68 (1H, dd, J=8.9 Hz, 2.3 Hz, ArH), 5.82 (1H, br s, NH),4.08-3.99 (4H, m, OCH₂), 3.83 (3H, s, OCH₃), 3.69-3.63 (4H, m, CH₂),2.39 (3H, s, CH₃), 1.25-1.20 (6H, t, J=7.0 Hz, CH₃). ³¹P NMR (CDCl₃,H₃PO₄ as external reference): δ 22.75

EXAMPLE 316 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows.

[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid

This product was prepared using methods similar to those describedherein, e.g., in Examples 251 and 276. MS (negative mode): 369.3 [M⁺−1].

EXAMPLE 317 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows.

2-{[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

Using methods similar to those described herein, e.g., in Example 261,the desired product was prepared, starting from Example 316. MS(positive mode): 546.3 [M⁺+1] & 568.3 [M⁺+Na].

EXAMPLE 318 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows:

2-({2-[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester

This product was prepared using methods analogous to those describedherein, e.g., in Examples 268 and 316, using2-[(2-amino-ethyl)-phenoxy-phosphinoylamino]-propionic acid ethyl esterin the reductive amination step. MS (positive mode): 559.4 [M⁺+1] &581.3 [M⁺+Na].

EXAMPLE 319 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows:

2-((1-Ethoxycarbonyl-ethylamino)-{2-[4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphinoylamino)-propionicacid ethyl ester

This product was prepared by methods analogous to those describedherein, e.g., in Example 318, using2-[(2-aminoethyl)-(1-ethoxycarbonyl-ethylamino)-phosphinoylamino]-propionicacid ethyl ester in the reductive amination step. MS (positive mode):582.4 [M⁺+1] & 604.3 [M⁺+Na].

EXAMPLE 320 Synthesis of Representative Compounds of Formula 66

Representative compounds of the invention can be prepared as illustratedabove. For example, a specific compound of Formula 66 can be prepared asfollows.

Rolipram can be treated in a solvent such as dimethylformamide ortetrahydrofuran with a base such as sodium hydride. When bubblingceases, E-1,4-dibromobutene is added in excess. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the mono-alkylated product isisolated by chromatography. The allylic bromide is then heated withtriethylphosphite in a solvent such as toluene to generate the diethylester of the desired phosphonic acid.

EXAMPLES 321-325

The synthetic sequence used in Examples 321-325 for preparingrepresentative compounds of the invention is illustrated above. In theabove illustration the substructure on the right below representsCyclosporin A.

EXAMPLE 321 Synthesis of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(diethoxyphosphoryl-methydroxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a mixture of cyclo-[[(2S, 3R, 4R,6E)-7-(4-hydroyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](113 mg, 0.088 mmol) and cesium carbonate (33 mg, 0.1 mmol) in DMF (1mL) was added trifluoromethanesulfonic acid diethoxyphosphorylmethylester (60 mg, 0.2 mmol). The mixture was stirred at room temperature for16 hours. The reaction was quenched with 2% aqueous lithium chloride andthe mixture was extracted with ethyl acetate. The ethyl acetate extractwas concentrated in vacuo. The residue was purified by silica gel columnchromatography to provide the desired product (310 mg, 83%) contaminatedwith the unreacted starting materials, which was further purified by RPHPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) witheluents of H₂O—CH₃CN. The fractions containing the desired product werepooled and concentrated to dryness (62 mg, 49%). MS (m/z) 1431.0 [M+H]⁺,1428.7 [M−H]⁻; ³¹P (121.4 MHz, CDCl₃) δ 19.5.

The intermediate compound cyclo-[[(2S, 3R, 4R,6E)-7-(4-hydroyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]was prepared as follows.

a. cyclo-[[(2S, 3R, 4R,6E)-7-(4-Acetoxyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryi-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

A mixture of cyclosporin A (360 mg, 0.3 mmol), 4-acetoxystyrene (730 mg,4.5 mmol) and(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidene)dichloro(O-isopropoxyphenylmethylene)ruthenium(Hoveyda-Grubbs catalyst, 20 mg, 0.032 mmol) in dichloromethane (1 mL)was purged with nitrogen and stirred under reflux for 16 hours. Aftercooling, the reaction mixture was purified by silica gel columnchromatography using MeOH—CH₂Cl₂ to provide the product as a solid (395mg, 99%). MS (m/z) 1322.9 [M+H]⁺, 1344.9 [M+Na]⁺; HPLC retention time3.3 min. (relative to 4.1 min. of cyclosporin A; Phenominex Synergi 4micron hydro-RP 80A 50×4.6 mm; solvents, 35% water and 65% acetonitrile;flow rate 2 mL/min.; column temperature 60° C.).

b. cyclo-[[(2S, 3R, 4R,6E)-7-(4-Hydroxyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

A solution of cyclo-[[(2S, 3R, 4R,6E)-7-(4-acetoxyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](385 mg, 0.29 mmol) and triethylamine (1 mL) in MeOH (10 mL) was stirredat ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography using MeOH—CH₂Cl₂ to provide the desired product (310 mg,83%). MS (m/z) 1280.9 [M+H]⁺, 1278.8 [M−H]⁻; HPLC retention time 1.6min. (relative to 4.0 min. of cyclosporin A; Phenominex Synergi 4 micronhydro-RP 80A 50×4.6 mm; solvents, 35% water and 65% acetonitrile; flowrate 2 mL/min.; column temperature 60° C.).

EXAMPLE 322 Synthesis of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(dibenzyloxy-phosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a mixture of cyclo-[[(2S, 3R, 4R,6E)-7-(4-hydroyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](300 mg, 0.234 mmol) and cesium carbonate (326 mg, 1 mmol) in DMF (2 mL)was added trifluoromethanesulfonic acid dibenzyloxy-phosphorylmethylester (60 mg, 0.2 mmol). The mixture was stirred at room temperature for16 hours. The reaction mixture was filtered through Acrodisc (13 mmsyringe filter with 0.45 micron Nylon membrane) and purified by RP HPLCusing a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) witheluents of H₂O—CH₃CN. The fractions containing the desired product werepooled and concentrated to dryness, affording a white solid (115 mg,32%). MS (m/z) 1554.9 [M+H]⁺, 1552.7 [M−H]⁻; ³¹P (121.4 MHz, CDCl₃) δ20.5.

EXAMPLE 323 Synthesis of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(dihydroxy-phosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a mixture of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(dibenzyloxyphosphoryl-methoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](115 mg, 0.074 mmol) and 2,6-lutidine (40 μL, 0.35 mmol) indichloromethane (2 mL) was added trimethylsilyl bromide (50 μL, 0.35mmol). The mixture was stirred at room temperature for 2 hours. Thereaction was quenched with methanol (1 mL) and the mixture wasconcentrated. The residue was treated with a solution of ammoniumfluoride (0.5 M, 2 mL), stirred for 1 hour, concentrated, andpartitioned between dichloromethane and 1 N HCl. The dichloromethanelayer was concentrated and the crude product was purified by RP HPLCusing a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) witheluents of 0.1% TFA H₂O-0.1% TFA CH₃CN. The fractions containing thedesired product were pooled and concentrated to dryness, affording ahygroscopic solid (68 mg, 63%). MS (m/z) 1374.9 [M+H]⁺, 1373.1 [M−H]⁻;HPLC retention time 0.3 min. (relative to 4.0 min. of cyclosporin A;Phenominex Synergi 4 micron hydro-RP 80A 50×4.6 mm; solvents, 35% waterand 65% acetonitrile; flow rate 2 mL/min.; column temperature 60° C.).

EXAMPLE 324 Synthesis of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(1-(S)-ethoxycarbonylethoxy)phenoxyphosphoryl-methoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

A mixture of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(dihydroxyphosphorylmethoxy)-phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](34 mg, 0.023 mmol), phenol (22 mg, 0.23 mmol), dicyclohexylcarbodiimide(47 mg, 0.23 mmol) and 4-(N,N-dimethylamino)pyridine (5.6 mg, 0.046mmol) in DMF (2 mL) was stirred at 140° C. for 20 min. After cooling,the monophenyl monophosphonic acid product was purified by RP HPLC usinga Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of0.1% TFA H₂O-0.1% TFA CH₃CN. MS (m/z) 1450.9 [M+H]⁺, 1449.1 [M−H]⁻; ³¹P(121.4 MHz, CDCl₃) δ 14.9. This intermediate was mixed with ethyl(S)-(−)-lactate (40 mg, 0.34 mmol), PyBOP (80 mg, 0.15 mmol),diisopropylethylamine (45 μL, 0.26 mmol) and DMF (1.7 mL). The resultingmixture was stirred at room temperature for 2 hours. After removal ofinsoluble impurities, the crude product was purified by RP HPLC using aPhenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of0.1% TFA H₂O-0.1% TFA CH₃CN. The desired fractions were pooled andpartitioned between acetonitrile and saturated aqueous sodiumbicarbonate. The organic layer was concentrated to afford the product asa solid (12 mg, 34%). MS (m/z) 1573.1 [M+Na]⁺, 1548.8 [M−H]⁻; ³¹P (121.4MHz, CDCl₃) δ 15.3 and 17.4.

EXAMPLE 325 Synthesis of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(1-(S)-hydroxycarbonylethoxy)hydoxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a solution of cyclo-[[(2S, 3R, 4R,6E)-7-(4-(1-(S)-ethoxycarbonyl-ethoxy)phenoxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-(6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](5mg, 3.2 μmol) in a mixed solvent of water and acetonitrile (0.5 mL and4.5 mL) was added 1 N NaOH (40 μL). The solutions was stirred at roomtemperature for 2 hours. The resulting reaction mixture was concentratedand purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80Acolumn (50×21.2 mm) with eluents of 0.1% TFA R₂O-0.1% TFA CH₃CN. Thedesired fraction was concentrated to dryness affording the product as asolid (1.5 mg, 32%). MS (m/z) 1446.9 [M+H]⁺, 1444.9 [M−H]⁻; HPLCretention time 0.2 min. (relative to 4.0 min. of cyclosporin A;Phenominex Synergi 4 micron hydro-RP 80A 50×4.6 mm; solvents, 35% waterand 65% acetonitrile; flow rate 2 mL/min.; column temperature 60° C.).

EXAMPLE 326 Synthesis of Representative compounds of the Invention

A protection-deprotection sequence in which the 20-ketone group ofRimexolone is protected to afford the derivative 326.2 is illustratedabove. The ketone is protected, for example, by conversion to the cyclicethylene ketal, by reaction in toluene solution at reflux temperaturewith ethylene glycol and an acid catalyst, as described in J. Am. Chem.Soc., 77:1904(1955). Deprotection is effected by reaction withpyridinium tosylate in aqueous acetone, as described in J. Chem. Soc.,Chem. Comm., 1351 (1987).

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone 326.1 with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 50:102(1970). The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 101, 5841(1979).

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate 326.1 is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc., Chem. Comm., 406(1983), to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The protected compound 326.2 is then converted into thephosphonate-containing analog 326.3, using the procedures describedbelow, and the protecting group or groups are then removed, as describedabove, to give the phosphonate 326.4.

EXAMPLE 327 Synthesis of Representative compounds of the Invention

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the ketone-protected derivative327.1 is reacted with an amine or hydroxylamine 327.2, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime 327.3. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 86:133(1978). and in J. Mass. Spectrom., 30:497(1995). Theprotecting group is then removed to afford the 20-keto phosphonateproduct 327.4.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated above. In this procedure, a phosphonate 327.5,in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 327.6(Aldrich) to produce the ether 327.7. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 327.8. The above procedure is also employed for the preparation ofsubstituted hydroxylamines which are precursors to phosphonates.

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate 327.1, in which the 20-ketone is protected as the dimethylhydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine 327.8a, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime 327.10. Deprotectionaffords the 20-keto phosphonate 327.11. The oxime forming reaction istypically performed at ambient temperature in ethanol-acetic acidsolution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether 327.8a, different oxime ethers 327.2, the corresponding products327.4 are obtained.

The preparation of compounds in which the phosphonate group is attachedby means of a benzyloxy oxime group is illustrated above. In thisprocedure, the dienone 327.1, in which the 20-ketone is protected as thedimethyl hydrazone, is reacted, as described above, withO-(3-bromobenzyl)hydroxylamine 327.9, prepared as described above from3-bromobenzyl bromide and BOC-protected hydroxylamine 327.6, to give theoxime 327.12. The protecting group is then removed to yield the 20-ketoproduct 327.13. The latter product is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite 327.14 to afford thephosphonate 327.15. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 35:1371(1992). The reaction is performed atca. 100° C. in an inert solvent such as toluene, in the presence of abase such as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 327.13 is coupled with a dialkylpropenylphosphonate 327.16 (Aldrich) to afford the phosphonate 327.17.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry, 503ff (Plenum, 2001) and in Acc. Chem. Res.,12:146(1979). The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)-palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 327.17 isreduced, for example by reaction with diimide, to produce the saturatedanalog 327.18. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations, 6ff (VCH, 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromobenzylreagent 327.9, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 327.15, 327.17 and 327.18 areobtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of a 4-furylimino group is illustrated above. In this procedure,the substrate 327.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with a dialkyl 4-amino-2-furyl phosphonate327.20, prepared by the palladium catalyzed coupling reaction, asdescribed above, between 4-amino-2-bromofuran (Tet., 43:3295(1987)) anda dialkyl phosphite, to give, after deprotection, the imine product327.21. The imine forming reaction is conducted in a hydrocarbon solventsuch as toluene or xylene, at reflux temperature, in the presence of abasic catalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the 4-aminofurylphosphonate 327.20 different amino-substituted aryl or heteroarylphosphonates, products analogous to 327.21 are obtained.

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an amide linkage is illustrated above. Inthis procedure, the dienone 327.1, in which the 20-ketone is protectedas the dimethylhydrazone, is reacted with 2-carboxyethyl hydroxylamine327.22 (J. Med. Chem., 33:1423(1990)) to yield the oxime 327.23. Thereaction of steroidal 1,4-dien-3-ones with hydroxylamines is describedin J. Steroid Bioch., 7:795(1976); the reaction is performed betweenequimolar amounts of the reactants in a polar organic solvent such aspyridine or methanol, optionally in the presence of acetic acid orsodium acetate. The product 327.23 is then coupled with a dialkyl4-aminophenyl phosphonate 327.24 (Epsilon) and dicyclohexylcarbodiimide, to yield, after deprotection, the amide oxime 327.25. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in S. R. Sandler and W. Karo, Organic FunctionalGroup Preparations, 274(Academic Press, 1968), and R. C. Larock,Comprehensive Organic Transformations, 972ff (VCH, 1989). The carboxylicacid is reacted with the amine in the presence of an activating agent,such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

Using the above procedures, but employing, in place of thecarboxy-substituted hydroxylamine 327.22, different carboxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates, theproducts analogous to 327.25 are obtained.

EXAMPLE 328 Synthesis of Representative Compounds of the Invention

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and/or a variablecarbon chain is illustrated above. In this procedure, the dienone 326.1is reduced to afford the 1,2-dihydro product 328.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 44:602(2001). The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc.,86:1520(1964), to afford the 2-formyl product 328.2. This compound isthen reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 328.3,in which the substituent X is either a phosphonate group or a groupwhich is subsequently transformed into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxyl and the like. The reaction yields the isomeric 2′- and 1′-arylpyrazoles 328.4 and 328.5. The pyrazole-forming reaction is performedbetween equimolar amounts of the reactants in an acidic solvent such asacetic acid, as described in J. Am. Chem. Soc., 86:1520(1964). Thepyrazoles 328.4 and 328.5 are then transformed into the phosphonates328.6 and 328.7. Optionally, the reduction and formylation reactions areperformed on the substrate 326.2 in which the 20-ketone is protected asthe cyclic ethylene ketal.

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl ring and an alkoxy group is illustrated above. In thisprocedure, the ketoaldehyde 328.2 is reacted, as described above, with3-hydroxyphenyl hydrazine 328.8 (JP 03011081) to give the pyrazoles328.9 and 328.10. The 2′-substituted isomer 328.9 is then reacted indimethylformamide solution at 70° with one molar equivalent of a dialkyl2-bromoethyl phosphonate 328.11 (Aldrich) and potassium carbonate, togive the ethoxy phosphonate 328.12.

The isomeric pyrazole 328.10 is reacted in a Mitsonobu with one molarequivalent of a dialkyl 3-hydroxypropyl phosphonate 328.13 (Zh. Obschei.Khim., 44:1834(1974)) to yield the phosphonate 328.14. The preparationof aromatic ethers by means of the Mitsonobu reaction is described, forexample, in R. C. Larock, Comprehensive Organic Transformations, 448(VCH, 1989), and in F. A. Carey and R. J. Sundberg, Advanced OrganicChemistry, Part B, 153-4(Plenum, 2001) and in Org. React., 42:335(1992).The phenol and the alcohol or thiol component are reacted together in anaprotic solvent such as, for example, tetrahydrofuran, in the presenceof a dialkyl azodicarboxylate and a triarylphosphine, to afford theether or thioether products. The procedure is also described in Org.React., 42:335-656(1992).

Using the above procedures, but employing different hydroxy-substitutedhydrazines, and/or different bromo or hydroxy-substituted phosphonates,the products analogous to 328.12 and 328.14 are obtained.

The preparation of the phosphonates in which the phosphonate group isattached by means of an amino or a carbamate group and an aromatic ringis illustrated above. In this procedure, the ketoaldehyde 328.2 isreacted, as described above, with 4-aminophenyl hydrazine 328.15 (Syn.Comm., 4:57(1974)) to produce the pyrazoles 328.16 and 328.17. The2′-substituted isomer 328.16 is then reacted in dimethylformamidesolution at 700 with one molar equivalent of a dialkyl 3-bromopropylphosphonate 328.18 (J. Amer. Chem. Soc., 122:1554(2000)) and cesiumcarbonate, to give the amine phosphonate 328.19.

Alternatively, the 1-substituted pyrazole 328.22 is coupled with adialkyl 4-hydroxymethylphenyl phosphonate 328.20 (U.S. Pat. No.5,569,664) and carbonyl diimidazole to prepare the carbamate phosphonate328.21. The preparation of carbamates is described in ComprehensiveOrganic Functional Group Transformations, A. R. Katritzky, ed.,Pergamon, 1995, Vol. 6, p 416ff, and in Organic Functional GroupPreparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p.260ff. In the procedure, the amine is reacted in an inert aproticsolvent such as dichloromethane or tetrahydrofuran, with phosgene or afunctional equivalent thereof, such as carbonyl diimidazole,triphosgene, pentafluorophenyl carbonate and the like, to afford thecorresponding activated acylamine. The latter compound is then reactedwith an alcohol to yield the carbamate. Using the above procedures, butemploying, in place of the aminophenyl hydrazine 328.15, differentamino-substituted hydrazines, and/or different dialkyl bromo orhydroxy-substituted phosphonates, the products analogous to thecompounds 328.19 and 328.21 are obtained.

EXAMPLE 329 Synthesis of Representative compounds of the Invention

The phosphonate esters in which the phosphonate group is attached bymeans of a variable carbon linkage is illustrated above. In thisprocedure, the ketoaldehyde 328.2 is reacted with hydrazine to affordthe pyrazole derivative 329.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 329.2, in which R² and X are as defined above, or a reactivebromoheteroaromatic reagent, to yield the alkylation products 329.3 and329.4. The alkylation of substituted pyrazoles is described, forexample, in Heterocyclic Chemistry, by T. L. Gilchrist, Longman, 1992,p. 309. The reaction is performed between equimolar amounts of thesubstrates in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 329.3 and 329.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates 329.5 and 329.6, usingthe procedures described herein.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 329.1 is reacted in dimethylformamide solution at70° C. with one molar equivalent of a dialkyl 4-bromobutenyl phosphonate329.7 (J. Med. Chem., 1992, 35, 1371) and lithium hexamethyl disilazide,to give the pyrazoles 329.8 and 329.9.

Using the above procedures, but employing different bromo-substitutedphosphonates, the products analogous to 329.8 and 329.9 are obtained.

Representative compounds of the invention can be prepared as illustratedabove. The pyrazole 329.1 is reacted in tetrahydrofuran solution with2,5-bis(bromomethyl)furan 329.10 (Tet., 1999, 55, 4709) and potassiumhexamethyl disilazide, to give the alkylation products 329.11 and329.12. The 2′-substituted isomer 329.11 is then reacted, in a Arbuzovreaction, with a trialkyl phosphite to yield the phosphonate 329.13. TheArbuzov reaction is described in Handb. Organophosphorus Chem., 1992,115. In this procedure, in which a bromo substituent is converted intothe corresponding phosphonate, the substrate is heated at from about 60°to about 160° with a five to fifty-fold molar excess of a trialkylphosphite, to effect the transformation.

The 1-substituted pyrazole 329.12 is reacted at ambient temperature indimethylformamide solution with one molar equivalent of a dialkylmercaptomethyl phosphonate 329.14 (J. Med. Chem., 1985, 26, 1688) andcesium carbonate, to give the thioether phosphonate 329.15.

Using the above procedures, but employing different dihalides, and/ordifferent mercapto-substituted phosphonates, the products analogous to329.13 and 329.15 are obtained.

EXAMPLE 330 Synthesis of Representative compounds of the Invention

A representative compound of the invention 330.4 can be prepared asillustrated above and as described below.

Compound 303.3 (250 mg, 0.65 mmol) was dissolved in 10 mL of absoluteethanol (15 mL) under an argon atmosphere. Following the addition ofNaOH (29 mg, 0.72 mmol), the reaction mixture was stirred overnight atroom temperature. TLC (CHCl₃/MeOH, 9:1) showed completion of reaction.The reaction mixture was concentrated to a solid and dissolved in ethylacetate (20 mL). The solution was washed with deionized water (2×10 mL)and dried over Na₂SO₄. Concentration gave a solid that was purified bysilica gel column chromatography (CHCl₃/MeOH, 4:1), affording purecompound 330.4 as a solid (188 mg, 75%). ESI-MS m/z 383 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆): δ 7.32 (1H, s, ArH), 6.96 (2H, s, ArH), 4.31 (2H, d,J=9.9 Hz, OCH₂), 4.18-4.08 (4H, m, 2×OCH₂), 2.08 (3H, s, CH₃), 2.00 (3H,s, CH₃), 1.26 (6H, t, J=7.0 Hz, CH₃). 31P NMR (121.7 MHz,DMSO-d₆/external H₃PO₄) β ppm 20.0-20.4 (m); HPLC: 93% pure (Sphereclone5 μL, H₂O:MeCN, 20 min linear from 10-90% MeCN, 1.0 mL/min).

The intermediate compound 330.3 was prepared as follows.

a. Synthesis of Compound 330.1. 2-Methyl-5-nitrophenol (2.00 g, 13.05mmol) was dissolved in dry DMF (10 mL) under argon atmosphere and cooledto 0° C. Diethylphosponomethyl-O-triflate (4.70 gm, 15.66 mmol) andcesium carbonate (6.38 gm, 19.58 mmol) were added sequentially. Thereaction mixture was stirred at 0° C. for 4 hrs. TLC (cyclohexane/EtOAc,1:1) showed completion of reaction. Deionized water (15 mL) was addedand the mixture was extracted with EtOAC (2×50 mL). The organic layerwas washed with 1N HCl (20 mL) followed by water (2×20 mL), dried overNa₂SO₄ and concentrated to a semi-solid. Purification by silica gelcolumn chromatography (cyclohexane/EtOAc, 1:1) afforded pure compound330.1 as an oil (3.86 g, 97%).

ESI-MS m/z 304 [M+H]⁺.

b. Synthesis of Compound 330.2. Compound 330.1 (2.8 g, 9.24 mmol) wasdissolved in 15 mL of absolute ethanol (15 mL) and 6N HCl (2 mL) underan argon atmosphere. Following the addition of SnCl₂ 2H₂O (5.26 g, 27.72mmol), the reaction mixture was stirred overnight at room temperature.TLC (CHCl₃/MeOH, 9:1) showed completion of reaction. The mixture wasconcentrated to a semi-solid and dissolved in ethyl acetate (30 mL). Theethyl acetate layer was washed with deionized water (10 mL) and satd.NaHCO₃ (10 mL) and dried over Na₂SO₄. Concentration gave a solid thatwas used without purification. ESI-MS m/z 274 [M+H]⁺.

c. Synthesis of Compound 330.3. Crude compound K-105-48 (900 mg, 3.38mmol) was dissolved in 15 mL of dry THF (15 mL) under an argonatmosphere. Following the addition of 5-methylisoxazole-4-carboxylicacid (381 mg, 3.00 mmol) and diisopropyl carbodiimide (511 μL, 3.30mmol), the reaction mixture was stirred 6 h at room temperature. TLC(CHCl₃/MeOH, 9:1) showed completion of reaction. The reaction mixturewas filtered and the filtrate concentrated to give a solid, which wasdissolved in ethyl acetate (25 mL). The solution was washed withdeionized water (2×10 mL) and dried over Na₂SO₄. Concentration gave asolid that was purified by silica gel column chromatography (CHCl₃/MeOH,95:5) to afford pure compound 330.3 as light yellow solid (680 mg, 55%).ESI-MS m/z 383 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.11 (1H, s, ArH),7.06 (2H, s, ArH), 4.29-4.20 (4H, m, OCH₂), 4.14 (2H, d, J=10.4 Hz,OCH₂), 2.76 (3H, s, CH₃), 2.14 (3H, s, CH₃), 1.37 (6H, t, J=7.0 Hz,CH₃). ³¹P NMR (121.7 MHz, DMSO-d₆/external H₃PO₄) 5 ppm 19.7-20.0 (m);HPLC: 98% pure (Sphereclone 5/L, H₂O:MeCN, min linear from 10-90% MeCN,1.0 mL/min).

EXAMPLE 331 Synthesis of Representative Prednisone Compounds of theInvention

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-21 hydroxy group is accomplished throughalkylation of prednisone 331.1 with the appropriate phosphonate toprovide compounds of the invention 331.2. A specific compound of theinvention can be prepared as follows.

After sodium hydride extraction of the primary hydroxy proton in 331.1,diethyl phosphonate triflate is added to afford ether 331.4.

EXAMPLE 332 Synthesis of Representative Prednisone Compounds of theInvention

Representative compounds of the invention 332.3 can be prepared asillustrated above. Protection of prednisone 332.1 at the less hinderedprimary site furnishes alcohol 332.5, which is alkylated at the exposedhydroxy group with the appropriate phosphonate to provide 332.6. Removalof the protecting group completes the construction of analog 332.3. Aspecific compound can be prepared as follows.

Prednisone 332.1 is mono-protected as its TBS ether 332.7. Afteralkylating with the diethyl phosphonate triflate, the resultingintermediate 332.8 is treated with TBAF to give the desired phosphonate332.9.

EXAMPLE 333

By way of example and not limitation, embodiments of the invention arenamed below in tabular format (Table 100). These embodiments are of thegeneral formula “MBF”:

Each embodiment of MBF is depicted as a substituted nucleus (Sc). Sc isdescribed in formula 1-296 herein, wherein A⁰ is the point of covalentattachment of Sc to Lg, as well as in Tables 1.1 to 1.5 below. For thoseembodiments described in Table 100, Sc is a nucleus designated by anumber and each substituent is designated in order by letter or number.Tables 1.1 to 1.5 are a schedule of nuclei used in forming theembodiments of Table 100. Each nucleus (Sc) is given a numberdesignation from Tables 1.1 to 1.5, and this designation appears firstin each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to20.36 list the selected linking groups (Lg) and prodrug (Pd¹ and Pd²)substituents, again by letter or number designation, respectively.Accordingly, a compound of the formula MBF includes compounds having Scgroups based on formula 1-296 herein as well as compounds according toTable 100 below. In all cases, compounds of the formula MBF have groupsLg, Pd¹ and Pd² setforth in the Tables below.

Accordingly, each named embodiment of Table 100 is depicted by a numberdesignating the nucleus from Table 1.1-1.5, followed by a letterdesignating the linking group (Lg) from Table 10.1-10.19, and twonumbers designating the two prodrug groups (Pd¹ and Pd²) from Table20.1-20.36. In graphical tabular form, each embodiment of Table 100appears as a name having the syntax:

-   -   Sc.Lg.Pd¹.Pd²

Each Sc group is shown having a tilda (“˜”). The tilda is the point ofcovalent attachment of Sc to Lg. Q¹ and Q² of the linking groups (Lg),it should be understood, do not represent groups or atoms but are simplyconnectivity designations. Q¹ is the site of the covalent bond to thenucleus (Sc) and Q² is the site of the covalent bond to the phosphorousatom of formula MBF. Each prodrug group (Pd¹ and Pd²) are covalentlybonded to the phosphorous atom of MBF at the tilda symbol (“˜”) or theA⁰ symbol. Some embodiments of Tables 10.1-10.19 and 20.1-20.36 may bedesignated as a combination of letters and numbers (Table 10.1-10.19) ornumber and letter (Table 20.1-20.36). For example there are Table 10entries for BJ1 and BJ2. In any event, entries of Table 10.1-10.19always begin with a letter and those of Table 20.1-20.36 always beginwith a number. When a nucleus (Sc) is shown enclosed within squarebrackets (“[ ]”) and a covalent bond extends outside the brackets, thepoint of covalent attachment of Sc to Lg may be at any substitutablesite on SC. Selection of the point of attachment is described herein. Byway of example and not limitation, the point of attachment is selectedfrom those depicted in the schemes and examples. TABLE 1.1

TABLE 1.2

TABLE 1.3

TABLE 1.4

TABLE 1.5

TABLE 10.1

TABLE 10.2

TABLE 10.3

TABLE 10.4

TABLE 10.5

TABLE 10.6

TABLE 10.7

TABLE 10.8

TABLE 10.9

TABLE 10.10

TABLE 10.11

TABLE 10.12

TABLE 10.13

TABLE 10.14

TABLE 10.15

TABLE 10.16

TABLE 10.17

TABLE 10.18

TABLE 10.19

TABLE 20.1

TABLE 20.2

TABLE 20.3

TABLE 20.4

TABLE 20.5

TABLE 20.6

TABLE 20.7

TABLE 20.8

TABLE 20.9

TABLE 20.10

TABLE 20.11

TABLE 20.12

TABLE 20.13

TABLE 20.14

TABLE 20.15

TABLE 20.16

TABLE 20.17

TABLE 20.18

TABLE 20.19

TABLE 20.20

TABLE 20.21

TABLE 20.22

TABLE 20.23

TABLE 20.24

TABLE 20.25

TABLE 20.26

TABLE 20.27

TABLE 20.28

TABLE 20.29

TABLE 20.30

TABLE 20.31

TABLE 20.32

TABLE 20.33

TABLE 20.34

TABLE 20.35

TABLE 20.36

TABLE 20.37

TABLE 100 Prodrugs of 1.B 1.B.228.228; 1.B.228.229; 1.B.228.230;1.B.228.231; 1.B.228.236; 1.B.228.237; 1.B.228.238; 1.B.228.239;1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169; 1.B.228.172;1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228; 1.B.229.229;1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237; 1.B.229.238;1.B.229.239; 1.B.229.154; 1.B.229.157; 1.B.229.166; 1.B.229.169;1.B.229.172; 1.B.229.175; 1.B.229.240; 1.B.229.244; 1.B.230.228;1.B.230.229; 1.B.230.230; 1.B.230.231; 1.B.230.236; 1.B.230.237;1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157; 1.B.230.166;1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240; 1.B.230.244;1.B.231.228; 1.B.231.229; 1.B.231.230; 1.B.231.231; 1.B.231.236;1.B.231.237; 1.B.231.238; 1.B.231.239; 1.B.231.154; 1.B.231.157;1.B.231.166; 1.B.231.169; 1.B.231.172; 1.B.231.175; 1.B.231.240;1.B.231.244; 1.B.236.228; 1.B.236.229; 1.B.236.230; 1.B.236.231;1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239; 1.B.236.154;1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172; 1.B.236.175;1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229; 1.B.237.230;1.B.237.231; 1.B.237.236; 1.B.237.237; 1.B.237.238; 1.B.237.239;1.B.237.154; 1.B.237.157; 1.B.237.166; 1.B.237.169; 1.B.237.172;1.B.237.175; 1.B.237.240; 1.B.237.244; 1.B.238.228; 1.B.238.229;1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237; 1.B.238.238;1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166; 1.B.238.169;1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244; 1.B.239.228;1.B.239.229; 1.B.239.230; 1.B.239.231; 1.B.239.236; 1.B.239.237;1.B.239.238; 1.B.239.239; 1.B.239.154; 1.B.239.157; 1.B.239.166;1.B.239.169; 1.B.239.172; 1.B.239.175; 1.B.239.240; 1.B.239.244;1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231; 1.B.154.236;1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154; 1.B.154.157;1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175; 1.B.154.240;1.B.154.244; 1.B.157.228; 1.B.157.229; 1.B.157.230; 1.B.157.231;1.B.157.236; 1.B.157.237; 1.B.157.238; 1.B.157.239; 1.B.157.154;1.B.157.157; 1.B.157.166; 1.B.157.169; 1.B.157.172; 1.B.157.175;1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B.166.229; 1.B.166.230;1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238; 1.B.166.239;1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169; 1.B.166.172;1.B.166.175; 1.B.166.240; 1.B.166.244; 1.B.169.228; 1.B.169.229;1.B.169.230; 1.B.169.231; 1.B.169.236; 1.B.169.237; 1.B.169.238;1.B.169.239; 1.B.169.154; 1.B.169.157; 1.B.169.166; 1.B.169.169;1.B.169.172; 1.B.169.175; 1.B.169.240; 1.B.169.244; 1.B.172.228;1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236; 1.B.172.237;1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157; 1.B.172.166;1.B.172.169; 1.B.172.172; 1.B.172.175; 1.B.172.240; 1.B.172.244;1.B.175.228; 1.B.175.229; 1.B.175.230; 1.B.175.231; 1.B.175.236;1.B.175.237; 1.B.175.238; 1.B.175.239; 1.B.175.154; 1.B.175.157;1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175; 1.B.175.240;1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230; 1.B.240.231;1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239; 1.B.240.154;1.B.240.157; 1.B.240.166; 1.B.240.169; 1.B.240.172; 1.B.240.175;1.B.240.240; 1.B.240.244; 1.B.244.228; 1.B.244.229; 1.B.244.230;1.B.244.231; 1.B.244.236; 1.B.244.237; 1.B.244.238; 1.B.244.239;1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169; 1.B.244.172;1.B.244.175; 1.B.244.240; 1.B.244.244; Prodrugs of 1.D 1.D.228.228;1.D.228.229; 1.D.228.230; 1.D.228.231; 1.D.228.236; 1.D.228.237;1.D.228.238; 1.D.228.239; 1.D.228.154; 1.D.228.157; 1.D.228.166;1.D.228.169; 1.D.228.172; 1.D.228.175; 1.D.228.240; 1.D.228.244;1.D.229.228; 1.D.229.229; 1.D.229.230; 1.D.229.231; 1.D.229.236;1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154; 1.D.229.157;1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175; 1.D.229.240;1.D.229.244; 1.D.230.228; 1.D.230.229; 1.D.230.230; 1.D.230.231;1.D.230.236; 1.D.230.237; 1.D.230.238; 1.D.230.239; 1.D.230.154;1.D.230.157; 1.D.230.166; 1.D.230.169; 1.D.230.172; 1.D.230.175;1.D.230.240; 1.D.230.244; 1.D.231.228; 1.D.231.229; 1.D.231.230;1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238; 1.D.231.239;1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169; 1.D.231.172;1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D.236.229;1.D.236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238;1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166; 1.D.236.169;1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244; 1.D.237.228;1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236; 1.D.237.237;1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157; 1.D.237.166;1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240; 1.D.237.244;1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236;1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154; 1.D.238.157;1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175; 1.D.238.240;1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230; 1.D.239.231;1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239; 1.D.239.154;1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175;1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230;1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238; 1.D.154.239;1.D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169; 1.D.154.172;1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228; 1.D.157.229;1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238;1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169;1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228;1.D.166.229; 1.D.166.230; 1.D.166.231; 1.D.166.236; 1.D.166.237;1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157; 1.D.166.166;1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240; 1.D.166.244;1.D.169.228; 1.D.169.229; 1.D.169.230; 1.D.169.231; 1.D.169.236;1.D.169.237; 1.D.169.238; 1.D.169.239; 1.D.169.154; 1.D.169.157;1.D.169.166; 1.D.169.169; 1.D.169.172; 1.D.169.175; 1.D.169.240;1.D.169.244; 1.D.172.228; 1.D.172.229; 1.D.172.230; 1.D.172.231;1.D.172.236; 1.D.172.237; 1.D.172.238; 1.D.172.239; 1.D.172.154;1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172; 1.D.172.175;1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D.175.229; 1.D.175.230;1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238; 1.D.175.239;1.D.175.154; 1.D.175.157; 1.D.175.166; 1.D.175.169; 1.D.175.172;1.D.175.175; 1.D.175.240; 1.D.175.244; 1.D.240.228; 1.D.240.229;1.D.240.230; 1.D.240.231; 1.D.240.236; 1.D.240.237; 1.D.240.238;1.D.240.239; 1.D.240.154; 1.D.240.157; 1.D.240.166; 1.D.240.169;1.D.240.172; 1.D.240.175; 1.D.240.240; 1.D.240.244; 1.D.244.228;1.D.244.229; 1.D.244.230; 1.D.244.231; 1.D.244.236; 1.D.244.237;1.D.244.238; 1.D.244.239; 1.D.244.154; 1.D.244.157; 1.D.244.166;1.D.244.169; 1.D.244.172; 1.D.244.175; 1.D.244.240; 1.D.244.244;Prodrugs of 1.E 1.E.228.228; 1.E.228.229; 1.E.228.230; 1.E.228.231;1.E.228.236; 1.E.228.237; 1.E.228.238; 1.E.228.239; 1.E.228.154;1.E.228.157; 1.E.228.166; 1.E.228.169; 1.E.228.172; 1.E.228.175;1.E.228.240; 1.E.228.244; 1.E.229.228; 1.E.229.229; 1.E.229.230;1.E.229.231; 1.E.229.236; 1.E.229.237; 1.E.229.238; 1.E.229.239;1.E.229.154; 1.E.229.157; 1.E.229.166; 1.E.229.169; 1.E.229.172;1.E.229.175; 1.E.229.240; 1.E.229.244; 1.E.230.228; 1.E.230.229;1.E.230.230; 1.E.230.231; 1.E.230.236; 1.E.230.237; 1.E.230.238;1.E.230.239; 1.E.230.154; 1.E.230.157; 1.E.230.166; 1.E.230.169;1.E.230.172; 1.E.230.175; 1.E.230.240; 1.E.230.244; 1.E.231.228;1.E.231.229; 1.E.231.230; 1.E.231.231; 1.E.231.236; 1.E.231.237;1.E.231.238; 1.E.231.239; 1.E.231.154; 1.E.231.157; 1.E.231.166;1.E.231.169; 1.E.231.172; 1.E.231.175; 1.E.231.240; 1.E.231.244;1.E.236.228; 1.E.236.229; 1.E.236.230; 1.E.236.231; 1.E.236.236;1.E.236.237; 1.E.236.238; 1.E.236.239; 1.E.236.154; 1.E.236.157;1.E.236.166; 1.E.236.169; 1.E.236.172; 1.E.236.175; 1.E.236.240;1.E.236.244; 1.E.237.228; 1.E.237.229; 1.E.237.230; 1.E.237.231;1.E.237.236; 1.E.237.237; 1.E.237.238; 1.E.237.239; 1.E.237.154;1.E.237.157; 1.E.237.166; 1.E.237.169; 1.E.237.172; 1.E.237.175;1.E.237.240; 1.E.237.244; 1.E.238.228; 1.E.238.229; 1.E.238.230;1.E.238.231; 1.E.238.236; 1.E.238.237; 1.E.238.238; 1.E.238.239;1.E.238.154; 1.E.238.157; 1.E.238.166; 1.E.238.169; 1.E.238.172;1.E.238.175; 1.E.238.240; 1.E.238.244; 1.E.239.228; 1.E.239.229;1.E.239.230; 1.E.239.231; 1.E.239.236; 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1.E.172.236; 1.E.172.237; 1.E.172.238;1.E.172.239; 1.E.172.154; 1.E.172.157; 1.E.172.166; 1.E.172.169;1.E.172.172; 1.E.172.175; 1.E.172.240; 1.E.172.244; 1.E.175.228;1.E.175.229; 1.E.175.230; 1.E.175.231; 1.E.175.236; 1.E.175.237;1.E.175.238; 1.E.175.239; 1.E.175.154; 1.E.175.157; 1.E.175.166;1.E.175.169; 1.E.175.172; 1.E.175.175; 1.E.175.240; 1.E.175.244;1.E.240.228; 1.E.240.229; 1.E.240.230; 1.E.240.231; 1.E.240.236;1.E.240.237; 1.E.240.238; 1.E.240.239; 1.E.240.154; 1.E.240.157;1.E.240.166; 1.E.240.169; 1.E.240.172; 1.E.240.175; 1.E.240.240;1.E.240.244; 1.E.244.228; 1.E.244.229; 1.E.244.230; 1.E.244.231;1.E.244.236; 1.E.244.237; 1.E.244.238; 1.E.244.239; 1.E.244.154;1.E.244.157; 1.E.244.166; 1.E.244.169; 1.E.244.172; 1.E.244.175;1.E.244.240; 1.E.244.244; Prodrugs of 1.G 1.G.228.228; 1.G.228.229;1.G.228.230; 1.G.228.231; 1.G.228.236; 1.G.228.237; 1.G.228.238;1.G.228.239; 1.G.228.154; 1.G.228.157; 1.G.228.166; 1.G.228.169;1.G.228.172; 1.G.228.175; 1.G.228.240; 1.G.228.244; 1.G.229.228;1.G.229.229; 1.G.229.230; 1.G.229.231; 1.G.229.236; 1.G.229.237;1.G.229.238; 1.G.229.239; 1.G.229.154; 1.G.229.157; 1.G.229.166;1.G.229.169; 1.G.229.172; 1.G.229.175; 1.G.229.240; 1.G.229.244;1.G.230.228; 1.G.230.229; 1.G.230.230; 1.G.230.231; 1.G.230.236;1.G.230.237; 1.G.230.238; 1.G.230.239; 1.G.230.154; 1.G.230.157;1.G.230.166; 1.G.230.169; 1.G.230.172; 1.G.230.175; 1.G.230.240;1.G.230.244; 1.G.231.228; 1.G.231.229; 1.G.231.230; 1.G.231.231;1.G.231.236; 1.G.231.237; 1.G.231.238; 1.G.231.239; 1.G.231.154;1.G.231.157; 1.G.231.166; 1.G.231.169; 1.G.231.172; 1.G.231.175;1.G.231.240; 1.G.231.244; 1.G.236.228; 1.G.236.229; 1.G.236.230;1.G.236.231; 1.G.236.236; 1.G.236.237; 1.G.236.238; 1.G.236.239;1.G.236.154; 1.G.236.157; 1.G.236.166; 1.G.236.169; 1.G.236.172;1.G.236.175; 1.G.236.240; 1.G.236.244; 1.G.237.228; 1.G.237.229;1.G.237.230; 1.G.237.231; 1.G.237.236; 1.G.237.237; 1.G.237.238;1.G.237.239; 1.G.237.154; 1.G.237.157; 1.G.237.166; 1.G.237.169;1.G.237.172; 1.G.237.175; 1.G.237.240; 1.G.237.244; 1.G.238.228;1.G.238.229; 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1.G.169.230; 1.G.169.231; 1.G.169.236; 1.G.169.237;1.G.169.238; 1.G.169.239; 1.G.169.154; 1.G.169.157; 1.G.169.166;1.G.169.169; 1.G.169.172; 1.G.169.175; 1.G.169.240; 1.G.169.244;1.G.172.228; 1.G.172.229; 1.G.172.230; 1.G.172.231; 1.G.172.236;1.G.172.237; 1.G.172.238; 1.G.172.239; 1.G.172.154; 1.G.172.157;1.G.172.166; 1.G.172.169; 1.G.172.172; 1.G.172.175; 1.G.172.240;1.G.172.244; 1.G.175.228; 1.G.175.229; 1.G.175.230; 1.G.175.231;1.G.175.236; 1.G.175.237; 1.G.175.238; 1.G.175.239; 1.G.175.154;1.G.175.157; 1.G.175.166; 1.G.175.169; 1.G.175.172; 1.G.175.175;1.G.175.240; 1.G.175.244; 1.G.240.228; 1.G.240.229; 1.G.240.230;1.G.240.231; 1.G.240.236; 1.G.240.237; 1.G.240.238; 1.G.240.239;1.G.240.154; 1.G.240.157; 1.G.240.166; 1.G.240.169; 1.G.240.172;1.G.240.175; 1.G.240.240; 1.G.240.244; 1.G.244.228; 1.G.244.229;1.G.244.230; 1.G.244.231; 1.G.244.236; 1.G.244.237; 1.G.244.238;1.G.244.239; 1.G.244.154; 1.G.244.157; 1.G.244.166; 1.G.244.169;1.G.244.172; 1.G.244.175; 1.G.244.240; 1.G.244.244; Prodrugs of 1.I1.I.228.228; 1.I.228.229; 1.I.228.230; 1.I.228.231; 1.I.228.236;1.I.228.237; 1.I.228.238; 1.I.228.239; 1.I.228.154; 1.I.228.157;1.I.228.166; 1.I.228.169; 1.I.228.172; 1.I.228.175; 1.I.228.240;1.I.228.244; 1.I.229.228; 1.I.229.229; 1.I.229.230; 1.I.229.231;1.I.229.236; 1.I.229.237; 1.I.229.238; 1.I.229.239; 1.I.229.154;1.I.229.157; 1.I.229.166; 1.I.229.169; 1.I.229.172; 1.I.229.175;1.I.229.240; 1.I.229.244; 1.I.230.228; 1.I.230.229; 1.I.230.230;1.I.230.231; 1.I.230.236; 1.I.230.237; 1.I.230.238; 1.I.230.239;1.I.230.154; 1.I.230.157; 1.I.230.166; 1.I.230.169; 1.I.230.172;1.I.230.175; 1.I.230.240; 1.I.230.244; 1.I.231.228; 1.I.231.229;1.I.231.230; 1.I.231.231; 1.I.231.236; 1.I.231.237; 1.I.231.238;1.I.231.239; 1.I.231.154; 1.I.231.157; 1.I.231.166; 1.I.231.169;1.I.231.172; 1.I.231.175; 1.I.231.240; 1.I.231.244; 1.I.236.228;1.I.236.229; 1.I.236.230; 1.I.236.231; 1.I.236.236; 1.I.236.237;1.I.236.238; 1.I.236.239; 1.I.236.154; 1.I.236.157; 1.I.236.166;1.I.236.169; 1.I.236.172; 1.I.236.175; 1.I.236.240; 1.I.236.244;1.I.237.228; 1.I.237.229; 1.I.237.230; 1.I.237.231; 1.I.237.236;1.I.237.237; 1.I.237.238; 1.I.237.239; 1.I.237.154; 1.I.237.157;1.I.237.166; 1.I.237.169; 1.I.237.172; 1.I.237.175; 1.I.237.240;1.I.237.244; 1.I.238.228; 1.I.238.229; 1.I.238.230; 1.I.238.231;1.I.238.236; 1.I.238.237; 1.I.238.238; 1.I.238.239; 1.I.238.154;1.I.238.157; 1.I.238.166; 1.I.238.169; 1.I.238.172; 1.I.238.175;1.I.238.240; 1.I.238.244; 1.I.239.228; 1.I.239.229; 1.I.239.230;1.I.239.231; 1.I.239.236; 1.I.239.237; 1.I.239.238; 1.I.239.239;1.I.239.154; 1.I.239.157; 1.I.239.166; 1.I.239.169; 1.I.239.172;1.I.239.175; 1.I.239.240; 1.I.239.244; 1.I.154.228; 1.I.154.229;1.I.154.230; 1.I.154.231; 1.I.154.236; 1.I.154.237; 1.I.154.238;1.I.154.239; 1.I.154.154; 1.I.154.157; 1.I.154.166; 1.I.154.169;1.I.154.172; 1.I.154.175; 1.I.154.240; 1.I.154.244; 1.I.157.228;1.I.157.229; 1.I.157.230; 1.I.157.231; 1.I.157.236; 1.I.157.237;1.I.157.238; 1.I.157.239; 1.I.157.154; 1.I.157.157; 1.I.157.166;1.I.157.169; 1.I.157.172; 1.I.157.175; 1.I.157.240; 1.I.157.244;1.I.166.228; 1.I.166.229; 1.I.166.230; 1.I.166.231; 1.I.166.236;1.I.166.237; 1.I.166.238; 1.I.166.239; 1.I.166.154; 1.I.166.157;1.I.166.166; 1.I.166.169; 1.I.166.172; 1.I.166.175; 1.I.166.240;1.I.166.244; 1.I.169.228; 1.I.169.229; 1.I.169.230; 1.I.169.231;1.I.169.236; 1.I.169.237; 1.I.169.238; 1.I.169.239; 1.I.169.154;1.I.169.157; 1.I.169.166; 1.I.169.169; 1.I.169.172; 1.I.169.175;1.I.169.240; 1.I.169.244; 1.I.172.228; 1.I.172.229; 1.I.172.230;1.I.172.231; 1.I.172.236; 1.I.172.237; 1.I.172.238; 1.I.172.239;1.I.172.154; 1.I.172.157; 1.I.172.166; 1.I.172.169; 1.I.172.172;1.I.172.175; 1.I.172.240; 1.I.172.244; 1.I.175.228; 1.I.175.229;1.I.175.230; 1.I.175.231; 1.I.175.236; 1.I.175.237; 1.I.175.238;1.I.175.239; 1.I.175.154; 1.I.175.157; 1.I.175.166; 1.I.175.169;1.I.175.172; 1.I.175.175; 1.I.175.240; 1.I.175.244; 1.I.240.228;1.I.240.229; 1.I.240.230; 1.I.240.231; 1.I.240.236; 1.I.240.237;1.I.240.238; 1.I.240.239; 1.I.240.154; 1.I.240.157; 1.I.240.166;1.I.240.169; 1.I.240.172; 1.I.240.175; 1.I.240.240; 1.I.240.244;1.I.244.228; 1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236;1.I.244.237; 1.I.244.238; 1.I.244.239; 1.I.244.154; 1.I.244.157;1.I.244.166; 1.I.244.169; 1.I.244.172; 1.I.244.175; 1.I.244.240;1.I.244.244; Prodrugs of 1.J 1.J.228.228; 1.J.228.229; 1.J.228.230;1.J.228.231; 1.J.228.236; 1.J.228.237; 1.J.228.238; 1.J.228.239;1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169; 1.J.228.172;1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229;1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238;1.J.229.239; 1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169;1.J.229.172; 1.J.229.175; 1.J.229.240; 1.J.229.244; 1.J.230.228;1.J.230.229; 1.J.230.230; 1.J.230.231; 1.J.230.236; 1.J.230.237;1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157; 1.J.230.166;1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244;1.J.231.228; 1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236;1.J.231.237; 1.J.231.238; 1.J.231.239; 1.J.231.154; 1.J.231.157;1.J.231.166; 1.J.231.169; 1.J.231.172; 1.J.231.175; 1.J.231.240;1.J.231.244; 1.J.236.228; 1.J.236.229; 1.J.236.230; 1.J.236.231;1.J.236.236; 1.J.236.237; 1.J.236.238; 1.J.236.239; 1.J.236.154;1.J.236.157; 1.J.236.166; 1.J.236.169; 1.J.236.172; 1.J.236.175;1.J.236.240; 1.J.236.244; 1.J.237.228; 1.J.237.229; 1.J.237.230;1.J.237.231; 1.J.237.236; 1.J.237.237; 1.J.237.238; 1.J.237.239;1.J.237.154; 1.J.237.157; 1.J.237.166; 1.J.237.169; 1.J.237.172;1.J.237.175; 1.J.237.240; 1.J.237.244; 1.J.238.228; 1.J.238.229;1.J.238.230; 1.J.238.231; 1.J.238.236; 1.J.238.237; 1.J.238.238;1.J.238.239; 1.J.238.154; 1.J.238.157; 1.J.238.166; 1.J.238.169;1.J.238.172; 1.J.238.175; 1.J.238.240; 1.J.238.244; 1.J.239.228;1.J.239.229; 1.J.239.230; 1.J.239.231; 1.J.239.236; 1.J.239.237;1.J.239.238; 1.J.239.239; 1.J.239.154; 1.J.239.157; 1.J.239.166;1.J.239.169; 1.J.239.172; 1.J.239.175; 1.J.239.240; 1.J.239.244;1.J.154.228; 1.J.154.229; 1.J.154.230; 1.J.154.231; 1.J.154.236;1.J.154.237; 1.J.154.238; 1.J.154.239; 1.J.154.154; 1.J.154.157;1.J.154.166; 1.J.154.169; 1.J.154.172; 1.J.154.175; 1.J.154.240;1.J.154.244; 1.J.157.228; 1.J.157.229; 1.J.157.230; 1.J.157.231;1.J.157.236; 1.J.157.237; 1.J.157.238; 1.J.157.239; 1.J.157.154;1.J.157.157; 1.J.157.166; 1.J.157.169; 1.J.157.172; 1.J.157.175;1.J.157.240; 1.J.157.244; 1.J.166.228; 1.J.166.229; 1.J.166.230;1.J.166.231; 1.J.166.236; 1.J.166.237; 1.J.166.238; 1.J.166.239;1.J.166.154; 1.J.166.157; 1.J.166.166; 1.J.166.169; 1.J.166.172;1.J.166.175; 1.J.166.240; 1.J.166.244; 1.J.169.228; 1.J.169.229;1.J.169.230; 1.J.169.231; 1.J.169.236; 1.J.169.237; 1.J.169.238;1.J.169.239; 1.J.169.154; 1.J.169.157; 1.J.169.166; 1.J.169.169;1.J.169.172; 1.J.169.175; 1.J.169.240; 1.J.169.244; 1.J.172.228;1.J.172.229; 1.J.172.230; 1.J.172.231; 1.J.172.236; 1.J.172.237;1.J.172.238; 1.J.172.239; 1.J.172.154; 1.J.172.157; 1.J.172.166;1.J.172.169; 1.J.172.172; 1.J.172.175; 1.J.172.240; 1.J.172.244;1.J.175.228; 1.J.175.229; 1.J.175.230; 1.J.175.231; 1.J.175.236;1.J.175.237; 1.J.175.238; 1.J.175.239; 1.J.175.154; 1.J.175.157;1.J.175.166; 1.J.175.169; 1.J.175.172; 1.J.175.175; 1.J.175.240;1.J.175.244; 1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231;1.J.240.236; 1.J.240.237; 1.J.240.238; 1.J.240.239; 1.J.240.154;1.J.240.157; 1.J.240.166; 1.J.240.169; 1.J.240.172; 1.J.240.175;1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229; 1.J.244.230;1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239;1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172;1.J.244.175; 1.J.244.240; 1.J.244.244; Prodrugs of 1.L 1.L.228.228;1.L.228.229; 1.L.228.230; 1.L.228.231; 1.L.228.236; 1.L.228.237;1.L.228.238; 1.L.228.239; 1.L.228.154; 1.L.228.157; 1.L.228.166;1.L.228.169; 1.L.228.172; 1.L.228.175; 1.L.228.240; 1.L.228.244;1.L.229.228; 1.L.229.229; 1.L.229.230; 1.L.229.231; 1.L.229.236;1.L.229.237; 1.L.229.238; 1.L.229.239; 1.L.229.154; 1.L.229.157;1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175; 1.L.229.240;1.L.229.244; 1.L.230.228; 1.L.230.229; 1.L.230.230; 1.L.230.231;1.L.230.236; 1.L.230.237; 1.L.230.238; 1.L.230.239; 1.L.230.154;1.L.230.157; 1.L.230.166; 1.L.230.169; 1.L.230.172; 1.L.230.175;1.L.230.240; 1.L.230.244; 1.L.231.228; 1.L.231.229; 1.L.231.230;1.L.231.231; 1.L.231.236; 1.L.231.237; 1.L.231.238; 1.L.231.239;1.L.231.154; 1.L.231.157; 1.L.231.166; 1.L.231.169; 1.L.231.172;1.L.231.175; 1.L.231.240; 1.L.231.244; 1.L.236.228; 1.L.236.229;1.L.236.230; 1.L.236.231; 1.L.236.236; 1.L.236.237; 1.L.236.238;1.L.236.239; 1.L.236.154; 1.L.236.157; 1.L.236.166; 1.L.236.169;1.L.236.172; 1.L.236.175; 1.L.236.240; 1.L.236.244; 1.L.237.228;1.L.237.229; 1.L.237.230; 1.L.237.231; 1.L.237.236; 1.L.237.237;1.L.237.238; 1.L.237.239; 1.L.237.154; 1.L.237.157; 1.L.237.166;1.L.237.169; 1.L.237.172; 1.L.237.175; 1.L.237.240; 1.L.237.244;1.L.238.228; 1.L.238.229; 1.L.238.230; 1.L.238.231; 1.L.238.236;1.L.238.237; 1.L.238.238; 1.L.238.239; 1.L.238.154; 1.L.238.157;1.L.238.166; 1.L.238.169; 1.L.238.172; 1.L.238.175; 1.L.238.240;1.L.238.244; 1.L.239.228; 1.L.239.229; 1.L.239.230; 1.L.239.231;1.L.239.236; 1.L.239.237; 1.L.239.238; 1.L.239.239; 1.L.239.154;1.L.239.157; 1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175;1.L.239.240; 1.L.239.244; 1.L.154.228; 1.L.154.229; 1.L.154.230;1.L.154.231; 1.L.154.236; 1.L.154.237; 1.L.154.238; 1.L.154.239;1.L.154.154; 1.L.154.157; 1.L.154.166; 1.L.154.169; 1.L.154.172;1.L.154.175; 1.L.154.240; 1.L.154.244; 1.L.157.228; 1.L.157.229;1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237; 1.L.157.238;1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169;1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L.166.228;1.L.166.229; 1.L.166.230; 1.L.166.231; 1.L.166.236; 1.L.166.237;1.L.166.238; 1.L.166.239; 1.L.166.154; 1.L.166.157; 1.L.166.166;1.L.166.169; 1.L.166.172; 1.L.166.175; 1.L.166.240; 1.L.166.244;1.L.169.228; 1.L.169.229; 1.L.169.230; 1.L.169.231; 1.L.169.236;1.L.169.237; 1.L.169.238; 1.L.169.239; 1.L.169.154; 1.L.169.157;1.L.169.166; 1.L.169.169; 1.L.169.172; 1.L.169.175; 1.L.169.240;1.L.169.244; 1.L.172.228; 1.L.172.229; 1.L.172.230; 1.L.172.231;1.L.172.236; 1.L.172.237; 1.L.172.238; 1.L.172.239; 1.L.172.154;1.L.172.157; 1.L.172.166; 1.L.172.169; 1.L.172.172; 1.L.172.175;1.L.172.240; 1.L.172.244; 1.L.175.228; 1.L.175.229; 1.L.175.230;1.L.175.231; 1.L.175.236; 1.L.175.237; 1.L.175.238; 1.L.175.239;1.L.175.154; 1.L.175.157; 1.L.175.166; 1.L.175.169; 1.L.175.172;1.L.175.175; 1.L.175.240; 1.L.175.244; 1.L.240.228; 1.L.240.229;1.L.240.230; 1.L.240.231; 1.L.240.236; 1.L.240.237; 1.L.240.238;1.L.240.239; 1.L.240.154; 1.L.240.157; 1.L.240.166; 1.L.240.169;1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244; 1.L.244.228;1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237;1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166;1.L.244.169; 1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;Prodrugs of 1.O 1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231;1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1.O.228.154;1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.O.228.175;1.O.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230;1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239;1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172;1.O.229.175; 1.O.229.240; 1.O.229.244; 1.O.230.228; 1.O.230.229;1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238;1.O.230.239; 1.O.230.154; 1.O.230.157; 1.O.230.166; 1.O.230.169;1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228;1.O.231.229; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237;1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166;1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244;1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236;1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157;1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240;1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231;1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154;1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175;1.O.237.240; 1.O.237.244; 1.O.238.228; 1.O.238.229; 1.O.238.230;1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.O.238.239;1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172;1.O.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229;1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238;1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169;1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; 1.O.154.228;1.O.154.229; 1.O.154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237;1.O.154.238; 1.O.154.239; 1.O.154.154; 1.O.154.157; 1.O.154.166;1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244;1.O.157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236;1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154; 1.O.157.157;1.O.157.166; 1.O.157.169; 1.O.157.172; 1.O.157.175; 1.O.157.240;1.O.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231;1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154;1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175;1.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230;1.O.169.231; 1.O.169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239;1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172;1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229;1.O.172.230; 1.O.172.231; 1.O.172.236; 1.O.172.237; 1.O.172.238;1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169;1.O.172.172; 1.O.172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228;1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237;1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166;1.O.175.169; 1.O.175.172; 1.O.175.175; 1.O.175.240; 1.O.175.244;1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236;1.O.240.237; 1.O.240.238; 1.O.240.239; 1.O.240.154; 1.O.240.157;1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240;1.O.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231;1.O.244.236; 1.O.244.237; 1.O.244.238; 1.O.244.239; 1.O.244.154;1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175;1.O.244.240; 1.O.244.244; Prodrugs of 1.P 1.P.228.228; 1.P.228.229;1.P.228.230; 1.P.228.231; 1.P.228.236; 1.P.228.237; 1.P.228.238;1.P.228.239; 1.P.228.154; 1.P.228.157; 1.P.228.166; 1.P.228.169;1.P.228.172; 1.P.228.175; 1.P.228.240; 1.P.228.244; 1.P.229.228;1.P.229.229; 1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237;1.P.229.238; 1.P.229.239; 1.P.229.154; 1.P.229.157; 1.P.229.166;1.P.229.169; 1.P.229.172; 1.P.229.175; 1.P.229.240; 1.P.229.244;1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231; 1.P.230.236;1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157;1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240;1.P.230.244; 1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231;1.P.231.236; 1.P.231.237; 1.P.231.238; 1.P.231.239; 1.P.231.154;1.P.231.157; 1.P.231.166; 1.P.231.169; 1.P.231.172; 1.P.231.175;1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229; 1.P.236.230;1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239;1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172;1.P.236.175; 1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229;1.P.237.230; 1.P.237.231; 1.P.237.236; 1.P.237.237; 1.P.237.238;1.P.237.239; 1.P.237.154; 1.P.237.157; 1.P.237.166; 1.P.237.169;1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244; 1.P.238.228;1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237;1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166;1.P.238.169; 1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244;1.P.239.228; 1.P.239.229; 1.P.239.230; 1.P.239.231; 1.P.239.236;1.P.239.237; 1.P.239.238; 1.P.239.239; 1.P.239.154; 1.P.239.157;1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175; 1.P.239.240;1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231;1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154;1.P.154.157; 1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175;1.P.154.240; 1.P.154.244; 1.P.157.228; 1.P.157.229; 1.P.157.230;1.P.157.231; 1.P.157.236; 1.P.157.237; 1.P.157.238; 1.P.157.239;1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169; 1.P.157.172;1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P.166.229;1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238;1.P.166.239; 1.P.166.154; 1.P.166.157; 1.P.166.166; 1.P.166.169;1.P.166.172; 1.P.166.175; 1.P.166.240; 1.P.166.244; 1.P.169.228;1.P.169.229; 1.P.169.230; 1.P.169.231; 1.P.169.236; 1.P.169.237;1.P.169.238; 1.P.169.239; 1.P.169.154; 1.P.169.157; 1.P.169.166;1.P.169.169; 1.P.169.172; 1.P.169.175; 1.P.169.240; 1.P.169.244;1.P.172.228; 1.P.172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236;1.P.172.237; 1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P.172.157;1.P.172.166; 1.P.172.169; 1.P.172.172; 1.P.172.175; 1.P.172.240;1.P.172.244; 1.P.175.228; 1.P.175.229; 1.P.175.230; 1.P.175.231;1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239; 1.P.175.154;1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175;1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230;1.P.240.231; 1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239;1.P.240.154; 1.P.240.157; 1.P.240.166; 1.P.240.169; 1.P.240.172;1.P.240.175; 1.P.240.240; 1.P.240.244; 1.P.244.228; 1.P.244.229;1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237; 1.P.244.238;1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169;1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244; Prodrugs of 1.U1.U.228.228; 1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236;1.U.228.237; 1.U.228.238; 1.U.228.239; 1.U.228.154; 1.U.228.157;1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240;1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231;1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154;1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175;1.U.229.240; 1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230;1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239;1.U.230.154; 1.U.230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172;1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229;1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238;1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169;1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228;1.U.236.229; 1.U.236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237;1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166;1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244;1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236;1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157;1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240;1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231;1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239; 1.U.238.154;1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175;1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230;1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239;1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172;1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229;1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238;1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169;1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228;1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237;1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166;1.U.157.169; 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244;1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1.U.166.236;1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154; 1.U.166.157;1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240;1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231;1.U.169.236; 1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154;1.U.169.157; 1.U.169.166; 1.U.169.169; 1.U.169.172; 1.U.169.175;1.U.169.240; 1.U.169.244; 1.U.172.228; 1.U.172.229; 1.U.172.230;1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238; 1.U.172.239;1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172;1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229;1.U.175.230; 1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238;1.U.175.239; 1.U.175.154; 1.U.175.157; 1.U.175.166; 1.U.175.169;1.U.175.172; 1.U.175.175; 1.U.175.240; 1.U.175.244; 1.U.240.228;1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236; 1.U.240.237;1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166;1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244;1.U.244.228; 1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236;1.U.244.237; 1.U.244.238; 1.U.244.239; 1.U.244.154; 1.U.244.157;1.U.244.166; 1.U.244.169; 1.U.244.172; 1.U.244.175; 1.U.244.240;1.U.244.244; Prodrugs of 1.W 1.W.228.228; 1.W.228.229; 1.W.228.230;1.W.228.231; 1.W.228.236; 1.W.228.237; 1.W.228.238; 1.W.228.239;1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169; 1.W.228.172;1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229;1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238;1.W.229.239; 1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169;1.W.229.172; 1.W.229.175; 1.W.229.240; 1.W.229.244; 1.W.230.228;1.W.230.229; 1.W.230.230; 1.W.230.231; 1.W.230.236; 1.W.230.237;1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157; 1.W.230.166;1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244;1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236;1.W.231.237; 1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157;1.W.231.166; 1.W.231.169; 1.W.231.172; 1.W.231.175; 1.W.231.240;1.W.231.244; 1.W.236.228; 1.W.236.229; 1.W.236.230; 1.W.236.231;1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239; 1.W.236.154;1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175;1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230;1.W.237.231; 1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239;1.W.237.154; 1.W.237.157; 1.W.237.166; 1.W.237.169; 1.W.237.172;1.W.237.175; 1.W.237.240; 1.W.237.244; 1.W.238.228; 1.W.238.229;1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237; 1.W.238.238;1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169;1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228;1.W.239.229; 1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237;1.W.239.238; 1.W.239.239; 1.W.239.154; 1.W.239.157; 1.W.239.166;1.W.239.169; 1.W.239.172; 1.W.239.175; 1.W.239.240; 1.W.239.244;1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231; 1.W.154.236;1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157;1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240;1.W.154.244; 1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231;1.W.157.236; 1.W.157.237; 1.W.157.238; 1.W.157.239; 1.W.157.154;1.W.157.157; 1.W.157.166; 1.W.157.169; 1.W.157.172; 1.W.157.175;1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229; 1.W.166.230;1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239;1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172;1.W.166.175; 1.W.166.240; 1.W.166.244; 1.W.169.228; 1.W.169.229;1.W.169.230; 1.W.169.231; 1.W.169.236; 1.W.169.237; 1.W.169.238;1.W.169.239; 1.W.169.154; 1.W.169.157; 1.W.169.166; 1.W.169.169;1.W.169.172; 1.W.169.175; 1.W.169.240; 1.W.169.244; 1.W.172.228;1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237;1.W.172.238; 1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166;1.W.172.169; 1.W.172.172; 1.W.172.175; 1.W.172.240; 1.W.172.244;1.W.175.228; 1.W.175.229; 1.W.175.230; 1.W.175.231; 1.W.175.236;1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154; 1.W.175.157;1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240;1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231;1.W.240.236; 1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154;1.W.240.157; 1.W.240.166; 1.W.240.169; 1.W.240.172; 1.W.240.175;1.W.240.240; 1.W.240.244; 1.W.244.228; 1.W.244.229; 1.W.244.230;1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238; 1.W.244.239;1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172;1.W.244.175; 1.W.244.240; 1.W.244.244; Prodrugs of 1.Y 1.Y.228.228;1.Y.228.229; 1.Y.228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237;1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166;1.Y.228.169; 1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244;1.Y.229.228; 1.Y.229.229; 1.Y.229.230; 1.Y.229.231; 1.Y.229.236;1.Y.229.237; 1.Y.229.238; 1.Y.229.239; 1.Y.229.154; 1.Y.229.157;1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175; 1.Y.229.240;1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231;1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154;1.Y.230.157; 1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175;1.Y.230.240; 1.Y.230.244; 1.Y.231.228; 1.Y.231.229; 1.Y.231.230;1.Y.231.231; 1.Y.231.236; 1.Y.231.237; 1.Y.231.238; 1.Y.231.239;1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169; 1.Y.231.172;1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229;1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238;1.Y.236.239; 1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169;1.Y.236.172; 1.Y.236.175; 1.Y.236.240; 1.Y.236.244; 1.Y.237.228;1.Y.237.229; 1.Y.237.230; 1.Y.237.231; 1.Y.237.236; 1.Y.237.237;1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157; 1.Y.237.166;1.Y.237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244;1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236;1.Y.238.237; 1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157;1.Y.238.166; 1.Y.238.169; 1.Y.238.172; 1.Y.238.175; 1.Y.238.240;1.Y.238.244; 1.Y.239.228; 1.Y.239.229; 1.Y.239.230; 1.Y.239.231;1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239; 1.Y.239.154;1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175;1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230;1.Y.154.231; 1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239;1.Y.154.154; 1.Y.154.157; 1.Y.154.166; 1.Y.154.169; 1.Y.154.172;1.Y.154.175; 1.Y.154.240; 1.Y.154.244; 1.Y.157.228; 1.Y.157.229;1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237; 1.Y.157.238;1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169;1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228;1.Y.166.229; 1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237;1.Y.166.238; 1.Y.166.239; 1.Y.166.154; 1.Y.166.157; 1.Y.166.166;1.Y.166.169; 1.Y.166.172; 1.Y.166.175; 1.Y.166.240; 1.Y.166.244;1.Y.169.228; 1.Y.169.229; 1.Y.169.230; 1.Y.169.231; 1.Y.169.236;1.Y.169.237; 1.Y.169.238; 1.Y.169.239; 1.Y.169.154; 1.Y.169.157;1.Y.169.166; 1.Y.169.169; 1.Y.169.172; 1.Y.169.175; 1.Y.169.240;1.Y.169.244; 1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231;1.Y.172.236; 1.Y.172.237; 1.Y.172.238; 1.Y.172.239; 1.Y.172.154;1.Y.172.157; 1.Y.172.166; 1.Y.172.169; 1.Y.172.172; 1.Y.172.175;1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229; 1.Y.175.230;1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239;1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172;1.Y.175.175; 1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229;1.Y.240.230; 1.Y.240.231; 1.Y.240.236; 1.Y.240.237; 1.Y.240.238;1.Y.240.239; 1.Y.240.154; 1.Y.240.157; 1.Y.240.166; 1.Y.240.169;1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244; 1.Y.244.228;1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237;1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166;1.Y.244.169; 1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;Prodrugs of 2.B 2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231;2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154;2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175;2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230;2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239;2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172;2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229;2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238;2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169;2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228;2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237;2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166;2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244;2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236;2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157;2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240;2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231;2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154;2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175;2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230;2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239;2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172;2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229;2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238;2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169;2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228;2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236; 2.B.154.237;2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166;2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244;2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236;2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157;2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240;2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231;2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154;2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175;2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230;2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239;2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172;2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229;2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238;2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169;2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228;2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237;2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166;2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244;2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236;2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157;2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240;2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231;2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154;2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175;2.B.244.240; 2.B.244.244; Prodrugs of 2.D 2.D.228.228; 2.D.228.229;2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238;2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169;2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228;2.D.229.229; 2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237;2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166;2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244;2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236;2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157;2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240;2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231;2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154;2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175;2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230;2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239;2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172;2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229;2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238;2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169;2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228;2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237;2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166;2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244;2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236;2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157;2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240;2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231;2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154;2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175;2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230;2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239;2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172;2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229;2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238;2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169;2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D.169.228;2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237;2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166;2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244;2.D.172.228; 2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236;2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157;2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240;2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231;2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154;2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175;2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230;2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239;2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172;2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229;2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238;2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169;2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244; Prodrugs of 2.E2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236;2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157;2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240;2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231;2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154;2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175;2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230;2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239;2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172;2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229;2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238;2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169;2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228;2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237;2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166;2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244;2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236;2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157;2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240;2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231;2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154;2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175;2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230;2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239;2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172;2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229;2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238;2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169;2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228;2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237;2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166;2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244;2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236;2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157;2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240;2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231;2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154;2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175;2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230;2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239;2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172;2.E.172.175; 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2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166;2.I.244.169; 2.I.244.172; 2.I.244.175; 2.I.244.240; 2.I.244.244;Prodrugs of 2.J 2.J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231;2.J.228.236; 2.J.228.237; 2.J.228.238; 2.J.228.239; 2.J.228.154;2.J.228.157; 2.J.228.166; 2.J.228.169; 2.J.228.172; 2.J.228.175;2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229; 2.J.229.230;2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239;2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172;2.J.229.175; 2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229;2.J.230.230; 2.J.230.231; 2.J.230.236; 2.J.230.237; 2.J.230.238;2.J.230.239; 2.J.230.154; 2.J.230.157; 2.J.230.166; 2.J.230.169;2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244; 2.J.231.228;2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237;2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166;2.J.231.169; 2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244;2.J.236.228; 2.J.236.229; 2.J.236.230; 2.J.236.231; 2.J.236.236;2.J.236.237; 2.J.236.238; 2.J.236.239; 2.J.236.154; 2.J.236.157;2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175; 2.J.236.240;2.J.236.244; 2.J.237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231;2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154;2.J.237.157; 2.J.237.166; 2.J.237.169; 2.J.237.172; 2.J.237.175;2.J.237.240; 2.J.237.244; 2.J.238.228; 2.J.238.229; 2.J.238.230;2.J.238.231; 2.J.238.236; 2.J.238.237; 2.J.238.238; 2.J.238.239;2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169; 2.J.238.172;2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229;2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238;2.J.239.239; 2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169;2.J.239.172; 2.J.239.175; 2.J.239.240; 2.J.239.244; 2.J.154.228;2.J.154.229; 2.J.154.230; 2.J.154.231; 2.J.154.236; 2.J.154.237;2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157; 2.J.154.166;2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244;2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236;2.J.157.237; 2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157;2.J.157.166; 2.J.157.169; 2.J.157.172; 2.J.157.175; 2.J.157.240;2.J.157.244; 2.J.166.228; 2.J.166.229; 2.J.166.230; 2.J.166.231;2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239; 2.J.166.154;2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175;2.J.166.240; 2.J.166.244; 2.J.169.228; 2.J.169.229; 2.J.169.230;2.J.169.231; 2.J.169.236; 2.J.169.237; 2.J.169.238; 2.J.169.239;2.J.169.154; 2.J.169.157; 2.J.169.166; 2.J.169.169; 2.J.169.172;2.J.169.175; 2.J.169.240; 2.J.169.244; 2.J.172.228; 2.J.172.229;2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237; 2.J.172.238;2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169;2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228;2.J.175.229; 2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237;2.J.175.238; 2.J.175.239; 2.J.175.154; 2.J.175.157; 2.J.175.166;2.J.175.169; 2.J.175.172; 2.J.175.175; 2.J.175.240; 2.J.175.244;2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231; 2.J.240.236;2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157;2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240;2.J.240.244; 2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231;2.J.244.236; 2.J.244.237; 2.J.244.238; 2.J.244.239; 2.J.244.154;2.J.244.157; 2.J.244.166; 2.J.244.169; 2.J.244.172; 2.J.244.175;2.J.244.240; 2.J.244.244; Prodrugs of 2.L 2.L.228.228; 2.L.228.229;2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238;2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169;2.L.228.172; 2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228;2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237;2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166;2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244;2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236;2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157;2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240;2.L.230.244; 2.L.231.228; 2.L.231.229; 2.L.231.230; 2.L.231.231;2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154;2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175;2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230;2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239;2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172;2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L.237.228; 2.L.237.229;2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238;2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166; 2.L.237.169;2.L.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228;2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237;2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166;2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244;2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236;2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157;2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240;2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231;2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154;2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175;2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L.157.229; 2.L.157.230;2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239;2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172;2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229;2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238;2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169;2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L.169.228;2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236; 2.L.169.237;2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166;2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244;2.L.172.228; 2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236;2.L.172.237; 2.L.172.238; 2.L.172.239; 2.L.172.154; 2.L.172.157;2.L.172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240;2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230; 2.L.175.231;2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154;2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175;2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230;2.L.240.231; 2.L.240.236; 2.L.240.237; 2.L.240.238; 2.L.240.239;2.L.240.154; 2.L.240.157; 2.L.240.166; 2.L.240.169; 2.L.240.172;2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228; 2.L.244.229;2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238;2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169;2.L.244.172; 2.L.244.175; 2.L.244.240; 2.L.244.244; Prodrugs of 2.O2.O.228.228; 2.O.228.229; 2.O.228.230; 2.O.228.231; 2.O.228.236;2.O.228.237; 2.O.228.238; 2.O.228.239; 2.O.228.154; 2.O.228.157;2.O.228.166; 2.O.228.169; 2.O.228.172; 2.O.228.175; 2.O.228.240;2.O.228.244; 2.O.229.228; 2.O.229.229; 2.O.229.230; 2.O.229.231;2.O.229.236; 2.O.229.237; 2.O.229.238; 2.O.229.239; 2.O.229.154;2.O.229.157; 2.O.229.166; 2.O.229.169; 2.O.229.172; 2.O.229.175;2.O.229.240; 2.O.229.244; 2.O.230.228; 2.O.230.229; 2.O.230.230;2.O.230.231; 2.O.230.236; 2.O.230.237; 2.O.230.238; 2.O.230.239;2.O.230.154; 2.O.230.157; 2.O.230.166; 2.O.230.169; 2.O.230.172;2.O.230.175; 2.O.230.240; 2.O.230.244; 2.O.231.228; 2.O.231.229;2.O.231.230; 2.O.231.231; 2.O.231.236; 2.O.231.237; 2.O.231.238;2.O.231.239; 2.O.231.154; 2.O.231.157; 2.O.231.166; 2.O.231.169;2.O.231.172; 2.O.231.175; 2.O.231.240; 2.O.231.244; 2.O.236.228;2.O.236.229; 2.O.236.230; 2.O.236.231; 2.O.236.236; 2.O.236.237;2.O.236.238; 2.O.236.239; 2.O.236.154; 2.O.236.157; 2.O.236.166;2.O.236.169; 2.O.236.172; 2.O.236.175; 2.O.236.240; 2.O.236.244;2.O.237.228; 2.O.237.229; 2.O.237.230; 2.O.237.231; 2.O.237.236;2.O.237.237; 2.O.237.238; 2.O.237.239; 2.O.237.154; 2.O.237.157;2.O.237.166; 2.O.237.169; 2.O.237.172; 2.O.237.175; 2.O.237.240;2.O.237.244; 2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231;2.O.238.236; 2.O.238.237; 2.O.238.238; 2.O.238.239; 2.O.238.154;2.O.238.157; 2.O.238.166; 2.O.238.169; 2.O.238.172; 2.O.238.175;2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229; 2.O.239.230;2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239;2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172;2.O.239.175; 2.O.239.240; 2.O.239.244; 2.O.154.228; 2.O.154.229;2.O.154.230; 2.O.154.231; 2.O.154.236; 2.O.154.237; 2.O.154.238;2.O.154.239; 2.O.154.154; 2.O.154.157; 2.O.154.166; 2.O.154.169;2.O.154.172; 2.O.154.175; 2.O.154.240; 2.O.154.244; 2.O.157.228;2.O.157.229; 2.O.157.230; 2.O.157.231; 2.O.157.236; 2.O.157.237;2.O.157.238; 2.O.157.239; 2.O.157.154; 2.O.157.157; 2.O.157.166;2.O.157.169; 2.O.157.172; 2.O.157.175; 2.O.157.240; 2.O.157.244;2.O.166.228; 2.O.166.229; 2.O.166.230; 2.O.166.231; 2.O.166.236;2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154; 2.O.166.157;2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240;2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231;2.O.169.236; 2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154;2.O.169.157; 2.O.169.166; 2.O.169.169; 2.O.169.172; 2.O.169.175;2.O.169.240; 2.O.169.244; 2.O.172.228; 2.O.172.229; 2.O.172.230;2.O.172.231; 2.O.172.236; 2.O.172.237; 2.O.172.238; 2.O.172.239;2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172;2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229;2.O.175.230; 2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238;2.O.175.239; 2.O.175.154; 2.O.175.157; 2.O.175.166; 2.O.175.169;2.O.175.172; 2.O.175.175; 2.O.175.240; 2.O.175.244; 2.O.240.228;2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236; 2.O.240.237;2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166;2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244;2.O.244.228; 2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236;2.O.244.237; 2.O.244.238; 2.O.244.239; 2.O.244.154; 2.O.244.157;2.O.244.166; 2.O.244.169; 2.O.244.172; 2.O.244.175; 2.O.244.240;2.O.244.244; Prodrugs of 2.P 2.P.228.228; 2.P.228.229; 2.P.228.230;2.P.228.231; 2.P.228.236; 2.P.228.237; 2.P.228.238; 2.P.228.239;2.P.228.154; 2.P.228.157; 2.P.228.166; 2.P.228.169; 2.P.228.172;2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229;2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238;2.P.229.239; 2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169;2.P.229.172; 2.P.229.175; 2.P.229.240; 2.P.229.244; 2.P.230.228;2.P.230.229; 2.P.230.230; 2.P.230.231; 2.P.230.236; 2.P.230.237;2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157; 2.P.230.166;2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244;2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236;2.P.231.237; 2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157;2.P.231.166; 2.P.231.169; 2.P.231.172; 2.P.231.175; 2.P.231.240;2.P.231.244; 2.P.236.228; 2.P.236.229; 2.P.236.230; 2.P.236.231;2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239; 2.P.236.154;2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175;2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230;2.P.237.231; 2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239;2.P.237.154; 2.P.237.157; 2.P.237.166; 2.P.237.169; 2.P.237.172;2.P.237.175; 2.P.237.240; 2.P.237.244; 2.P.238.228; 2.P.238.229;2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237; 2.P.238.238;2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169;2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228;2.P.239.229; 2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237;2.P.239.238; 2.P.239.239; 2.P.239.154; 2.P.239.157; 2.P.239.166;2.P.239.169; 2.P.239.172; 2.P.239.175; 2.P.239.240; 2.P.239.244;2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231; 2.P.154.236;2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157;2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240;2.P.154.244; 2.P.157.228; 2.P.157.229; 2.P.157.230; 2.P.157.231;2.P.157.236; 2.P.157.237; 2.P.157.238; 2.P.157.239; 2.P.157.154;2.P.157.157; 2.P.157.166; 2.P.157.169; 2.P.157.172; 2.P.157.175;2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P.166.229; 2.P.166.230;2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239;2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172;2.P.166.175; 2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229;2.P.169.230; 2.P.169.231; 2.P.169.236; 2.P.169.237; 2.P.169.238;2.P.169.239; 2.P.169.154; 2.P.169.157; 2.P.169.166; 2.P.169.169;2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244; 2.P.172.228;2.P.172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237;2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166;2.P.172.169; 2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244;2.P.175.228; 2.P.175.229; 2.P.175.230; 2.P.175.231; 2.P.175.236;2.P.175.237; 2.P.175.238; 2.P.175.239; 2.P.175.154; 2.P.175.157;2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175; 2.P.175.240;2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231;2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154;2.P.240.157; 2.P.240.166; 2.P.240.169; 2.P.240.172; 2.P.240.175;2.P.240.240; 2.P.240.244; 2.P.244.228; 2.P.244.229; 2.P.244.230;2.P.244.231; 2.P.244.236; 2.P.244.237; 2.P.244.238; 2.P.244.239;2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169; 2.P.244.172;2.P.244.175; 2.P.244.240; 2.P.244.244; Prodrugs of 2.U 2.U.228.228;2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237;2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166;2.U.228.169; 2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244;2.U.229.228; 2.U.229.229; 2.U.229.230; 2.U.229.231; 2.U.229.236;2.U.229.237; 2.U.229.238; 2.U.229.239; 2.U.229.154; 2.U.229.157;2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175; 2.U.229.240;2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231;2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154;2.U.230.157; 2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175;2.U.230.240; 2.U.230.244; 2.U.231.228; 2.U.231.229; 2.U.231.230;2.U.231.231; 2.U.231.236; 2.U.231.237; 2.U.231.238; 2.U.231.239;2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169; 2.U.231.172;2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229;2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238;2.U.236.239; 2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169;2.U.236.172; 2.U.236.175; 2.U.236.240; 2.U.236.244; 2.U.237.228;2.U.237.229; 2.U.237.230; 2.U.237.231; 2.U.237.236; 2.U.237.237;2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157; 2.U.237.166;2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244;2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236;2.U.238.237; 2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157;2.U.238.166; 2.U.238.169; 2.U.238.172; 2.U.238.175; 2.U.238.240;2.U.238.244; 2.U.239.228; 2.U.239.229; 2.U.239.230; 2.U.239.231;2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239; 2.U.239.154;2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175;2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230;2.U.154.231; 2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239;2.U.154.154; 2.U.154.157; 2.U.154.166; 2.U.154.169; 2.U.154.172;2.U.154.175; 2.U.154.240; 2.U.154.244; 2.U.157.228; 2.U.157.229;2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237; 2.U.157.238;2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169;2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228;2.U.166.229; 2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237;2.U.166.238; 2.U.166.239; 2.U.166.154; 2.U.166.157; 2.U.166.166;2.U.166.169; 2.U.166.172; 2.U.166.175; 2.U.166.240; 2.U.166.244;2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231; 2.U.169.236;2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157;2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240;2.U.169.244; 2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231;2.U.172.236; 2.U.172.237; 2.U.172.238; 2.U.172.239; 2.U.172.154;2.U.172.157; 2.U.172.166; 2.U.172.169; 2.U.172.172; 2.U.172.175;2.U.172.240; 2.U.172.244; 2.U.175.228; 2.U.175.229; 2.U.175.230;2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239;2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172;2.U.175.175; 2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229;2.U.240.230; 2.U.240.231; 2.U.240.236; 2.U.240.237; 2.U.240.238;2.U.240.239; 2.U.240.154; 2.U.240.157; 2.U.240.166; 2.U.240.169;2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244; 2.U.244.228;2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237;2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166;2.U.244.169; 2.U.244.172; 2.U.244.175; 2.U.244.240; 2.U.244.244;Prodrugs of 2.W 2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231;2.W.228.236; 2.W.228.237; 2.W.228.238; 2.W.228.239; 2.W.228.154;2.W.228.157; 2.W.228.166; 2.W.228.169; 2.W.228.172; 2.W.228.175;2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229; 2.W.229.230;2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239;2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172;2.W.229.175; 2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229;2.W.230.230; 2.W.230.231; 2.W.230.236; 2.W.230.237; 2.W.230.238;2.W.230.239; 2.W.230.154; 2.W.230.157; 2.W.230.166; 2.W.230.169;2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244; 2.W.231.228;2.W.231.229; 2.W.231.230; 2.W.231.231; 2.W.231.236; 2.W.231.237;2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166;2.W.231.169; 2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244;2.W.236.228; 2.W.236.229; 2.W.236.230; 2.W.236.231; 2.W.236.236;2.W.236.237; 2.W.236.238; 2.W.236.239; 2.W.236.154; 2.W.236.157;2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175; 2.W.236.240;2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231;2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154;2.W.237.157; 2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175;2.W.237.240; 2.W.237.244; 2.W.238.228; 2.W.238.229; 2.W.238.230;2.W.238.231; 2.W.238.236; 2.W.238.237; 2.W.238.238; 2.W.238.239;2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169; 2.W.238.172;2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229;2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238;2.W.239.239; 2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169;2.W.239.172; 2.W.239.175; 2.W.239.240; 2.W.239.244; 2.W.154.228;2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236; 2.W.154.237;2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166;2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244;2.W.157.228; 2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236;2.W.157.237; 2.W.157.238; 2.W.157.239; 2.W.157.154; 2.W.157.157;2.W.157.166; 2.W.157.169; 2.W.157.172; 2.W.157.175; 2.W.157.240;2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230; 2.W.166.231;2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154;2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175;2.W.166.240; 2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230;2.W.169.231; 2.W.169.236; 2.W.169.237; 2.W.169.238; 2.W.169.239;2.W.169.154; 2.W.169.157; 2.W.169.166; 2.W.169.169; 2.W.169.172;2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228; 2.W.172.229;2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238;2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169;2.W.172.172; 2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228;2.W.175.229; 2.W.175.230; 2.W.175.231; 2.W.175.236; 2.W.175.237;2.W.175.238; 2.W.175.239; 2.W.175.154; 2.W.175.157; 2.W.175.166;2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W.175.240; 2.W.175.244;2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236;2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157;2.W.240.166; 2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240;2.W.240.244; 2.W.244.228; 2.W.244.229; 2.W.244.230; 2.W.244.231;2.W.244.236; 2.W.244.237; 2.W.244.238; 2.W.244.239; 2.W.244.154;2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172; 2.W.244.175;2.W.244.240; 2.W.244.244; Prodrugs of 2.Y 2.Y.228.228; 2.Y.228.229;2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237; 2.Y.228.238;2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169;2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228;2.Y.229.229; 2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237;2.Y.229.238; 2.Y.229.239; 2.Y.229.154; 2.Y.229.157; 2.Y.229.166;2.Y.229.169; 2.Y.229.172; 2.Y.229.175; 2.Y.229.240; 2.Y.229.244;2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231; 2.Y.230.236;2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157;2.Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240;2.Y.230.244; 2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231;2.Y.231.236; 2.Y.231.237; 2.Y.231.238; 2.Y.231.239; 2.Y.231.154;2.Y.231.157; 2.Y.231.166; 2.Y.231.169; 2.Y.231.172; 2.Y.231.175;2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229; 2.Y.236.230;2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239;2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172;2.Y.236.175; 2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229;2.Y.237.230; 2.Y.237.231; 2.Y.237.236; 2.Y.237.237; 2.Y.237.238;2.Y.237.239; 2.Y.237.154; 2.Y.237.157; 2.Y.237.166; 2.Y.237.169;2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244; 2.Y.238.228;2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237;2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166;2.Y.238.169; 2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244;2.Y.239.228; 2.Y.239.229; 2.Y.239.230; 2.Y.239.231; 2.Y.239.236;2.Y.239.237; 2.Y.239.238; 2.Y.239.239; 2.Y.239.154; 2.Y.239.157;2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175; 2.Y.239.240;2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231;2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154;2.Y.154.157; 2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175;2.Y.154.240; 2.Y.154.244; 2.Y.157.228; 2.Y.157.229; 2.Y.157.230;2.Y.157.231; 2.Y.157.236; 2.Y.157.237; 2.Y.157.238; 2.Y.157.239;2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169; 2.Y.157.172;2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229;2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238;2.Y.166.239; 2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169;2.Y.166.172; 2.Y.166.175; 2.Y.166.240; 2.Y.166.244; 2.Y.169.228;2.Y.169.229; 2.Y.169.230; 2.Y.169.231; 2.Y.169.236; 2.Y.169.237;2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157; 2.Y.169.166;2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244;2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236;2.Y.172.237; 2.Y.172.238; 2.Y.172.239; 2.Y.172.154; 2.Y.172.157;2.Y.172.166; 2.Y.172.169; 2.Y.172.172; 2.Y.172.175; 2.Y.172.240;2.Y.172.244; 2.Y.175.228; 2.Y.175.229; 2.Y.175.230; 2.Y.175.231;2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239; 2.Y.175.154;2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175;2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230;2.Y.240.231; 2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239;2.Y.240.154; 2.Y.240.157; 2.Y.240.166; 2.Y.240.169; 2.Y.240.172;2.Y.240.175; 2.Y.240.240; 2.Y.240.244; 2.Y.244.228; 2.Y.244.229;2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237; 2.Y.244.238;2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169;2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244; Prodrugs of 3.B3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236;3.B.228.237; 3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157;3.B.228.166; 3.B.228.169; 3.B.228.172; 3.B.228.175; 3.B.228.240;3.B.228.244; 3.B.229.228; 3.B.229.229; 3.B.229.230; 3.B.229.231;3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239; 3.B.229.154;3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175;3.B.229.240; 3.B.229.244; 3.B.230.228; 3.B.230.229; 3.B.230.230;3.B.230.231; 3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239;3.B.230.154; 3.B.230.157; 3.B.230.166; 3.B.230.169; 3.B.230.172;3.B.230.175; 3.B.230.240; 3.B.230.244; 3.B.231.228; 3.B.231.229;3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237; 3.B.231.238;3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169;3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228;3.B.236.229; 3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237;3.B.236.238; 3.B.236.239; 3.B.236.154; 3.B.236.157; 3.B.236.166;3.B.236.169; 3.B.236.172; 3.B.236.175; 3.B.236.240; 3.B.236.244;3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231; 3.B.237.236;3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157;3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240;3.B.237.244; 3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231;3.B.238.236; 3.B.238.237; 3.B.238.238; 3.B.238.239; 3.B.238.154;3.B.238.157; 3.B.238.166; 3.B.238.169; 3.B.238.172; 3.B.238.175;3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229; 3.B.239.230;3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239;3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172;3.B.239.175; 3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229;3.B.154.230; 3.B.154.231; 3.B.154.236; 3.B.154.237; 3.B.154.238;3.B.154.239; 3.B.154.154; 3.B.154.157; 3.B.154.166; 3.B.154.169;3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244; 3.B.157.228;3.B.157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237;3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166;3.B.157.169; 3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244;3.B.166.228; 3.B.166.229; 3.B.166.230; 3.B.166.231; 3.B.166.236;3.B.166.237; 3.B.166.238; 3.B.166.239; 3.B.166.154; 3.B.166.157;3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175; 3.B.166.240;3.B.166.244; 3.B.169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231;3.B.169.236; 3.B.169.237; 3.B.169.238; 3.B.169.239; 3.B.169.154;3.B.169.157; 3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175;3.B.169.240; 3.B.169.244; 3.B.172.228; 3.B.172.229; 3.B.172.230;3.B.172.231; 3.B.172.236; 3.B.172.237; 3.B.172.238; 3.B.172.239;3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169; 3.B.172.172;3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229;3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238;3.B.175.239; 3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169;3.B.175.172; 3.B.175.175; 3.B.175.240; 3.B.175.244; 3.B.240.228;3.B.240.229; 3.B.240.230; 3.B.240.231; 3.B.240.236; 3.B.240.237;3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157; 3.B.240.166;3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244;3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236;3.B.244.237; 3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157;3.B.244.166; 3.B.244.169; 3.B.244.172; 3.B.244.175; 3.B.244.240;3.B.244.244; Prodrugs of 3.D 3.D.228.228; 3.D.228.229; 3.D.228.230;3.D.228.231; 3.D.228.236; 3.D.228.237; 3.D.228.238; 3.D.228.239;3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169; 3.D.228.172;3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229;3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238;3.D.229.239; 3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169;3.D.229.172; 3.D.229.175; 3.D.229.240; 3.D.229.244; 3.D.230.228;3.D.230.229; 3.D.230.230; 3.D.230.231; 3.D.230.236; 3.D.230.237;3.D.230.238; 3.D.230.239; 3.D.230.154; 3.D.230.157; 3.D.230.166;3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244;3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236;3.D.231.237; 3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157;3.D.231.166; 3.D.231.169; 3.D.231.172; 3.D.231.175; 3.D.231.240;3.D.231.244; 3.D.236.228; 3.D.236.229; 3.D.236.230; 3.D.236.231;3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239; 3.D.236.154;3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175;3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230;3.D.237.231; 3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239;3.D.237.154; 3.D.237.157; 3.D.237.166; 3.D.237.169; 3.D.237.172;3.D.237.175; 3.D.237.240; 3.D.237.244; 3.D.238.228; 3.D.238.229;3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237; 3.D.238.238;3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169;3.D.238.172; 3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228;3.D.239.229; 3.D.239.230; 3.D.239.231; 3.D.239.236; 3.D.239.237;3.D.239.238; 3.D.239.239; 3.D.239.154; 3.D.239.157; 3.D.239.166;3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240; 3.D.239.244;3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236;3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157;3.D.154.166; 3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240;3.D.154.244; 3.D.157.228; 3.D.157.229; 3.D.157.230; 3.D.157.231;3.D.157.236; 3.D.157.237; 3.D.157.238; 3.D.157.239; 3.D.157.154;3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172; 3.D.157.175;3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230;3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239;3.D.166.154; 3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172;3.D.166.175; 3.D.166.240; 3.D.166.244; 3.D.169.228; 3.D.169.229;3.D.169.230; 3.D.169.231; 3.D.169.236; 3.D.169.237; 3.D.169.238;3.D.169.239; 3.D.169.154; 3.D.169.157; 3.D.169.166; 3.D.169.169;3.D.169.172; 3.D.169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228;3.D.172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237;3.D.172.238; 3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166;3.D.172.169; 3.D.172.172; 3.D.172.175; 3.D.172.240; 3.D.172.244;3.D.175.228; 3.D.175.229; 3.D.175.230; 3.D.175.231; 3.D.175.236;3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154; 3.D.175.157;3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240;3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231;3.D.240.236; 3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154;3.D.240.157; 3.D.240.166; 3.D.240.169; 3.D.240.172; 3.D.240.175;3.D.240.240; 3.D.240.244; 3.D.244.228; 3.D.244.229; 3.D.244.230;3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238; 3.D.244.239;3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172;3.D.244.175; 3.D.244.240; 3.D.244.244; Prodrugs of 3.E 3.E.228.228;3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237;3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166;3.E.228.169; 3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244;3.E.229.228; 3.E.229.229; 3.E.229.230; 3.E.229.231; 3.E.229.236;3.E.229.237; 3.E.229.238; 3.E.229.239; 3.E.229.154; 3.E.229.157;3.E.229.166; 3.E.229.169; 3.E.229.172; 3.E.229.175; 3.E.229.240;3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231;3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154;3.E.230.157; 3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175;3.E.230.240; 3.E.230.244; 3.E.231.228; 3.E.231.229; 3.E.231.230;3.E.231.231; 3.E.231.236; 3.E.231.237; 3.E.231.238; 3.E.231.239;3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169; 3.E.231.172;3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229;3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238;3.E.236.239; 3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169;3.E.236.172; 3.E.236.175; 3.E.236.240; 3.E.236.244; 3.E.237.228;3.E.237.229; 3.E.237.230; 3.E.237.231; 3.E.237.236; 3.E.237.237;3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157; 3.E.237.166;3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244;3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236;3.E.238.237; 3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157;3.E.238.166; 3.E.238.169; 3.E.238.172; 3.E.238.175; 3.E.238.240;3.E.238.244; 3.E.239.228; 3.E.239.229; 3.E.239.230; 3.E.239.231;3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239; 3.E.239.154;3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175;3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230;3.E.154.231; 3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239;3.E.154.154; 3.E.154.157; 3.E.154.166; 3.E.154.169; 3.E.154.172;3.E.154.175; 3.E.154.240; 3.E.154.244; 3.E.157.228; 3.E.157.229;3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237; 3.E.157.238;3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169;3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228;3.E.166.229; 3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237;3.E.166.238; 3.E.166.239; 3.E.166.154; 3.E.166.157; 3.E.166.166;3.E.166.169; 3.E.166.172; 3.E.166.175; 3.E.166.240; 3.E.166.244;3.E.169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236;3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E.169.157;3.E.169.166; 3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240;3.E.169.244; 3.E.172.228; 3.E.172.229; 3.E.172.230; 3.E.172.231;3.E.172.236; 3.E.172.237; 3.E.172.238; 3.E.172.239; 3.E.172.154;3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172; 3.E.172.175;3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E.175.230;3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239;3.E.175.154; 3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172;3.E.175.175; 3.E.175.240; 3.E.175.244; 3.E.240.228; 3.E.240.229;3.E.240.230; 3.E.240.231; 3.E.240.236; 3.E.240.237; 3.E.240.238;3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166; 3.E.240.169;3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228;3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237;3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166;3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;Prodrugs of 3.G 3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231;3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3.G.228.154;3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175;3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229; 3.G.229.230;3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239;3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172;3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229;3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238;3.G.230.239; 3.G.230.154; 3.G.230.157; 3.G.230.166; 3.G.230.169;3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228;3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237;3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166;3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244;3.G.236.228; 3.G.236.229; 3.G.236.230; 3.G.236.231; 3.G.236.236;3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157;3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175; 3.G.236.240;3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231;3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154;3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175;3.G.237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230;3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238; 3.G.238.239;3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172;3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229;3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238;3.G.239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169;3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244; 3.G.154.228;3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237;3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157; 3.G.154.166;3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244;3.G.157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236;3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157;3.G.157.166; 3.G.157.169; 3.G.157.172; 3.G.157.175; 3.G.157.240;3.G.157.244; 3.G.166.228; 3.G.166.229; 3.G.166.230; 3.G.166.231;3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239; 3.G.166.154;3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175;3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230;3.G.169.231; 3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239;3.G.169.154; 3.G.169.157; 3.G.169.166; 3.G.169.169; 3.G.169.172;3.G.169.175; 3.G.169.240; 3.G.169.244; 3.G.172.228; 3.G.172.229;3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237; 3.G.172.238;3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169;3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228;3.G.175.229; 3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237;3.G.175.238; 3.G.175.239; 3.G.175.154; 3.G.175.157; 3.G.175.166;3.G.175.169; 3.G.175.172; 3.G.175.175; 3.G.175.240; 3.G.175.244;3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231; 3.G.240.236;3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157;3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240;3.G.240.244; 3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231;3.G.244.236; 3.G.244.237; 3.G.244.238; 3.G.244.239; 3.G.244.154;3.G.244.157; 3.G.244.166; 3.G.244.169; 3.G.244.172; 3.G.244.175;3.G.244.240; 3.G.244.244; Prodrugs of 3.I 3.I.228.228; 3.I.228.229;3.I.228.230; 3.I.228.231; 3.I.228.236; 3.I.228.237; 3.I.228.238;3.I.228.239; 3.I.228.154; 3.I.228.157; 3.I.228.166; 3.I.228.169;3.I.228.172; 3.I.228.175; 3.I.228.240; 3.I.228.244; 3.I.229.228;3.I.229.229; 3.I.229.230; 3.I.229.231; 3.I.229.236; 3.I.229.237;3.I.229.238; 3.I.229.239; 3.I.229.154; 3.I.229.157; 3.I.229.166;3.I.229.169; 3.I.229.172; 3.I.229.175; 3.I.229.240; 3.I.229.244;3.I.230.228; 3.I.230.229; 3.I.230.230; 3.I.230.231; 3.I.230.236;3.I.230.237; 3.I.230.238; 3.I.230.239; 3.I.230.154; 3.I.230.157;3.I.230.166; 3.I.230.169; 3.I.230.172; 3.I.230.175; 3.I.230.240;3.I.230.244; 3.I.231.228; 3.I.231.229; 3.I.231.230; 3.I.231.231;3.I.231.236; 3.I.231.237; 3.I.231.238; 3.I.231.239; 3.I.231.154;3.I.231.157; 3.I.231.166; 3.I.231.169; 3.I.231.172; 3.I.231.175;3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I.236.230;3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239;3.I.236.154; 3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172;3.I.236.175; 3.I.236.240; 3.I.236.244; 3.I.237.228; 3.I.237.229;3.I.237.230; 3.I.237.231; 3.I.237.236; 3.I.237.237; 3.I.237.238;3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166; 3.I.237.169;3.I.237.172; 3.I.237.175; 3.I.237.240; 3.I.237.244; 3.I.238.228;3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237;3.I.238.238; 3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166;3.I.238.169; 3.I.238.172; 3.I.238.175; 3.I.238.240; 3.I.238.244;3.I.239.228; 3.I.239.229; 3.I.239.230; 3.I.239.231; 3.I.239.236;3.I.239.237; 3.I.239.238; 3.I.239.239; 3.I.239.154; 3.I.239.157;3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240;3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231;3.I.154.236; 3.I.154.237; 3.I.154.238; 3.I.154.239; 3.I.154.154;3.I.154.157; 3.I.154.166; 3.I.154.169; 3.I.154.172; 3.I.154.175;3.I.154.240; 3.I.154.244; 3.I.157.228; 3.I.157.229; 3.I.157.230;3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238; 3.I.157.239;3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169; 3.I.157.172;3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229;3.I.166.230; 3.I.166.231; 3.I.166.236; 3.I.166.237; 3.I.166.238;3.I.166.239; 3.I.166.154; 3.I.166.157; 3.I.166.166; 3.I.166.169;3.I.166.172; 3.I.166.175; 3.I.166.240; 3.I.166.244; 3.I.169.228;3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236; 3.I.169.237;3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166;3.I.169.169; 3.I.169.172; 3.I.169.175; 3.I.169.240; 3.I.169.244;3.I.172.228; 3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236;3.I.172.237; 3.I.172.238; 3.I.172.239; 3.I.172.154; 3.I.172.157;3.I.172.166; 3.I.172.169; 3.I.172.172; 3.I.172.175; 3.I.172.240;3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230; 3.I.175.231;3.I.175.236; 3.I.175.237; 3.I.175.238; 3.I.175.239; 3.I.175.154;3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175;3.I.175.240; 3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230;3.I.240.231; 3.I.240.236; 3.I.240.237; 3.I.240.238; 3.I.240.239;3.I.240.154; 3.I.240.157; 3.I.240.166; 3.I.240.169; 3.I.240.172;3.I.240.175; 3.I.240.240; 3.I.240.244; 3.I.244.228; 3.I.244.229;3.I.244.230; 3.I.244.231; 3.I.244.236; 3.I.244.237; 3.I.244.238;3.I.244.239; 3.I.244.154; 3.I.244.157; 3.I.244.166; 3.I.244.169;3.I.244.172; 3.I.244.175; 3.I.244.240; 3.I.244.244; Prodrugs of 3.J3.J.228.228; 3.J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236;3.J.228.237; 3.J.228.238; 3.J.228.239; 3.J.228.154; 3.J.228.157;3.J.228.166; 3.J.228.169; 3.J.228.172; 3.J.228.175; 3.J.228.240;3.J.228.244; 3.J.229.228; 3.J.229.229; 3.J.229.230; 3.J.229.231;3.J.229.236; 3.J.229.237; 3.J.229.238; 3.J.229.239; 3.J.229.154;3.J.229.157; 3.J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175;3.J.229.240; 3.J.229.244; 3.J.230.228; 3.J.230.229; 3.J.230.230;3.J.230.231; 3.J.230.236; 3.J.230.237; 3.J.230.238; 3.J.230.239;3.J.230.154; 3.J.230.157; 3.J.230.166; 3.J.230.169; 3.J.230.172;3.J.230.175; 3.J.230.240; 3.J.230.244; 3.J.231.228; 3.J.231.229;3.J.231.230; 3.J.231.231; 3.J.231.236; 3.J.231.237; 3.J.231.238;3.J.231.239; 3.J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169;3.J.231.172; 3.J.231.175; 3.J.231.240; 3.J.231.244; 3.J.236.228;3.J.236.229; 3.J.236.230; 3.J.236.231; 3.J.236.236; 3.J.236.237;3.J.236.238; 3.J.236.239; 3.J.236.154; 3.J.236.157; 3.J.236.166;3.J.236.169; 3.J.236.172; 3.J.236.175; 3.J.236.240; 3.J.236.244;3.J.237.228; 3.J.237.229; 3.J.237.230; 3.J.237.231; 3.J.237.236;3.J.237.237; 3.J.237.238; 3.J.237.239; 3.J.237.154; 3.J.237.157;3.J.237.166; 3.J.237.169; 3.J.237.172; 3.J.237.175; 3.J.237.240;3.J.237.244; 3.J.238.228; 3.J.238.229; 3.J.238.230; 3.J.238.231;3.J.238.236; 3.J.238.237; 3.J.238.238; 3.J.238.239; 3.J.238.154;3.J.238.157; 3.J.238.166; 3.J.238.169; 3.J.238.172; 3.J.238.175;3.J.238.240; 3.J.238.244; 3.J.239.228; 3.J.239.229; 3.J.239.230;3.J.239.231; 3.J.239.236; 3.J.239.237; 3.J.239.238; 3.J.239.239;3.J.239.154; 3.J.239.157; 3.J.239.166; 3.J.239.169; 3.J.239.172;3.J.239.175; 3.J.239.240; 3.J.239.244; 3.J.154.228; 3.J.154.229;3.J.154.230; 3.J.154.231; 3.J.154.236; 3.J.154.237; 3.J.154.238;3.J.154.239; 3.J.154.154; 3.J.154.157; 3.J.154.166; 3.J.154.169;3.J.154.172; 3.J.154.175; 3.J.154.240; 3.J.154.244; 3.J.157.228;3.J.157.229; 3.J.157.230; 3.J.157.231; 3.J.157.236; 3.J.157.237;3.J.157.238; 3.J.157.239; 3.J.157.154; 3.J.157.157; 3.J.157.166;3.J.157.169; 3.J.157.172; 3.J.157.175; 3.J.157.240; 3.J.157.244;3.J.166.228; 3.J.166.229; 3.J.166.230; 3.J.166.231; 3.J.166.236;3.J.166.237; 3.J.166.238; 3.J.166.239; 3.J.166.154; 3.J.166.157;3.J.166.166; 3.J.166.169; 3.J.166.172; 3.J.166.175; 3.J.166.240;3.J.166.244; 3.J.169.228; 3.J.169.229; 3.J.169.230; 3.J.169.231;3.J.169.236; 3.J.169.237; 3.J.169.238; 3.J.169.239; 3.J.169.154;3.J.169.157; 3.J.169.166; 3.J.169.169; 3.J.169.172; 3.J.169.175;3.J.169.240; 3.J.169.244; 3.J.172.228; 3.J.172.229; 3.J.172.230;3.J.172.231; 3.J.172.236; 3.J.172.237; 3.J.172.238; 3.J.172.239;3.J.172.154; 3.J.172.157; 3.J.172.166; 3.J.172.169; 3.J.172.172;3.J.172.175; 3.J.172.240; 3.J.172.244; 3.J.175.228; 3.J.175.229;3.J.175.230; 3.J.175.231; 3.J.175.236; 3.J.175.237; 3.J.175.238;3.J.175.239; 3.J.175.154; 3.J.175.157; 3.J.175.166; 3.J.175.169;3.J.175.172; 3.J.175.175; 3.J.175.240; 3.J.175.244; 3.J.240.228;3.J.240.229; 3.J.240.230; 3.J.240.231; 3.J.240.236; 3.J.240.237;3.J.240.238; 3.J.240.239; 3.J.240.154; 3.J.240.157; 3.J.240.166;3.J.240.169; 3.J.240.172; 3.J.240.175; 3.J.240.240; 3.J.240.244;3.J.244.228; 3.J.244.229; 3.J.244.230; 3.J.244.231; 3.J.244.236;3.J.244.237; 3.J.244.238; 3.J.244.239; 3.J.244.154; 3.J.244.157;3.J.244.166; 3.J.244.169; 3.J.244.172; 3.J.244.175; 3.J.244.240;3.J.244.244; Prodrugs of 3.L 3.L.228.228; 3.L.228.229; 3.L.228.230;3.L.228.231; 3.L.228.236; 3.L.228.237; 3.L.228.238; 3.L.228.239;3.L.228.154; 3.L.228.157; 3.L.228.166; 3.L.228.169; 3.L.228.172;3.L.228.175; 3.L.228.240; 3.L.228.244; 3.L.229.228; 3.L.229.229;3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238;3.L.229.239; 3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169;3.L.229.172; 3.L.229.175; 3.L.229.240; 3.L.229.244; 3.L.230.228;3.L.230.229; 3.L.230.230; 3.L.230.231; 3.L.230.236; 3.L.230.237;3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157; 3.L.230.166;3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244;3.L.231.228; 3.L.231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236;3.L.231.237; 3.L.231.238; 3.L.231.239; 3.L.231.154; 3.L.231.157;3.L.231.166; 3.L.231.169; 3.L.231.172; 3.L.231.175; 3.L.231.240;3.L.231.244; 3.L.236.228; 3.L.236.229; 3.L.236.230; 3.L.236.231;3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239; 3.L.236.154;3.L.236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175;3.L.236.240; 3.L.236.244; 3.L.237.228; 3.L.237.229; 3.L.237.230;3.L.237.231; 3.L.237.236; 3.L.237.237; 3.L.237.238; 3.L.237.239;3.L.237.154; 3.L.237.157; 3.L.237.166; 3.L.237.169; 3.L.237.172;3.L.237.175; 3.L.237.240; 3.L.237.244; 3.L.238.228; 3.L.238.229;3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237; 3.L.238.238;3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169;3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228;3.L.239.229; 3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237;3.L.239.238; 3.L.239.239; 3.L.239.154; 3.L.239.157; 3.L.239.166;3.L.239.169; 3.L.239.172; 3.L.239.175; 3.L.239.240; 3.L.239.244;3.L.154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231; 3.L.154.236;3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157;3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240;3.L.154.244; 3.L.157.228; 3.L.157.229; 3.L.157.230; 3.L.157.231;3.L.157.236; 3.L.157.237; 3.L.157.238; 3.L.157.239; 3.L.157.154;3.L.157.157; 3.L.157.166; 3.L.157.169; 3.L.157.172; 3.L.157.175;3.L.157.240; 3.L.157.244; 3.L.166.228; 3.L.166.229; 3.L.166.230;3.L.166.231; 3.L.166.236; 3.L.166.237; 3.L.166.238; 3.L.166.239;3.L.166.154; 3.L.166.157; 3.L.166.166; 3.L.166.169; 3.L.166.172;3.L.166.175; 3.L.166.240; 3.L.166.244; 3.L.169.228; 3.L.169.229;3.L.169.230; 3.L.169.231; 3.L.169.236; 3.L.169.237; 3.L.169.238;3.L.169.239; 3.L.169.154; 3.L.169.157; 3.L.169.166; 3.L.169.169;3.L.169.172; 3.L.169.175; 3.L.169.240; 3.L.169.244; 3.L.172.228;3.L.172.229; 3.L.172.230; 3.L.172.231; 3.L.172.236; 3.L.172.237;3.L.172.238; 3.L.172.239; 3.L.172.154; 3.L.172.157; 3.L.172.166;3.L.172.169; 3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L.172.244;3.L.175.228; 3.L.175.229; 3.L.175.230; 3.L.175.231; 3.L.175.236;3.L.175.237; 3.L.175.238; 3.L.175.239; 3.L.175.154; 3.L.175.157;3.L.175.166; 3.L.175.169; 3.L.175.172; 3.L.175.175; 3.L.175.240;3.L.175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231;3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154;3.L.240.157; 3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175;3.L.240.240; 3.L.240.244; 3.L.244.228; 3.L.244.229; 3.L.244.230;3.L.244.231; 3.L.244.236; 3.L.244.237; 3.L.244.238; 3.L.244.239;3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169; 3.L.244.172;3.L.244.175; 3.L.244.240; 3.L.244.244; Prodrugs of 3.O 3.O.228.228;3.O.228.229; 3.O.228.230; 3.O.228.231; 3.O.228.236; 3.O.228.237;3.O.228.238; 3.O.228.239; 3.O.228.154; 3.O.228.157; 3.O.228.166;3.O.228.169; 3.O.228.172; 3.O.228.175; 3.O.228.240; 3.O.228.244;3.O.229.228; 3.O.229.229; 3.O.229.230; 3.O.229.231; 3.O.229.236;3.O.229.237; 3.O.229.238; 3.O.229.239; 3.O.229.154; 3.O.229.157;3.O.229.166; 3.O.229.169; 3.O.229.172; 3.O.229.175; 3.O.229.240;3.O.229.244; 3.O.230.228; 3.O.230.229; 3.O.230.230; 3.O.230.231;3.O.230.236; 3.O.230.237; 3.O.230.238; 3.O.230.239; 3.O.230.154;3.O.230.157; 3.O.230.166; 3.O.230.169; 3.O.230.172; 3.O.230.175;3.O.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.O.231.230;3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239;3.O.231.154; 3.O.231.157; 3.O.231.166; 3.O.231.169; 3.O.231.172;3.O.231.175; 3.O.231.240; 3.O.231.244; 3.O.236.228; 3.O.236.229;3.O.236.230; 3.O.236.231; 3.O.236.236; 3.O.236.237; 3.O.236.238;3.O.236.239; 3.O.236.154; 3.O.236.157; 3.O.236.166; 3.O.236.169;3.O.236.172; 3.O.236.175; 3.O.236.240; 3.O.236.244; 3.O.237.228;3.O.237.229; 3.O.237.230; 3.O.237.231; 3.O.237.236; 3.O.237.237;3.O.237.238; 3.O.237.239; 3.O.237.154; 3.O.237.157; 3.O.237.166;3.O.237.169; 3.O.237.172; 3.O.237.175; 3.O.237.240; 3.O.237.244;3.O.238.228; 3.O.238.229; 3.O.238.230; 3.O.238.231; 3.O.238.236;3.O.238.237; 3.O.238.238; 3.O.238.239; 3.O.238.154; 3.O.238.157;3.O.238.166; 3.O.238.169; 3.O.238.172; 3.O.238.175; 3.O.238.240;3.O.238.244; 3.O.239.228; 3.O.239.229; 3.O.239.230; 3.O.239.231;3.O.239.236; 3.O.239.237; 3.O.239.238; 3.O.239.239; 3.O.239.154;3.O.239.157; 3.O.239.166; 3.O.239.169; 3.O.239.172; 3.O.239.175;3.O.239.240; 3.O.239.244; 3.O.154.228; 3.O.154.229; 3.O.154.230;3.O.154.231; 3.O.154.236; 3.O.154.237; 3.O.154.238; 3.O.154.239;3.O.154.154; 3.O.154.157; 3.O.154.166; 3.O.154.169; 3.O.154.172;3.O.154.175; 3.O.154.240; 3.O.154.244; 3.O.157.228; 3.O.157.229;3.O.157.230; 3.O.157.231; 3.O.157.236; 3.O.157.237; 3.O.157.238;3.O.157.239; 3.O.157.154; 3.O.157.157; 3.O.157.166; 3.O.157.169;3.O.157.172; 3.O.157.175; 3.O.157.240; 3.O.157.244; 3.O.166.228;3.O.166.229; 3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237;3.O.166.238; 3.O.166.239; 3.O.166.154; 3.O.166.157; 3.O.166.166;3.O.166.169; 3.O.166.172; 3.O.166.175; 3.O.166.240; 3.O.166.244;3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231; 3.O.169.236;3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157;3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240;3.O.169.244; 3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231;3.O.172.236; 3.O.172.237; 3.O.172.238; 3.O.172.239; 3.O.172.154;3.O.172.157; 3.O.172.166; 3.O.172.169; 3.O.172.172; 3.O.172.175;3.O.172.240; 3.O.172.244; 3.O.175.228; 3.O.175.229; 3.O.175.230;3.O.175.231; 3.O.175.236; 3.O.175.237; 3.O.175.238; 3.O.175.239;3.O.175.154; 3.O.175.157; 3.O.175.166; 3.O.175.169; 3.O.175.172;3.O.175.175; 3.O.175.240; 3.O.175.244; 3.O.240.228; 3.O.240.229;3.O.240.230; 3.O.240.231; 3.O.240.236; 3.O.240.237; 3.O.240.238;3.O.240.239; 3.O.240.154; 3.O.240.157; 3.O.240.166; 3.O.240.169;3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244; 3.O.244.228;3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237;3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166;3.O.244.169; 3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;Prodrugs of 3.P 3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231;3.P.228.236; 3.P.228.237; 3.P.228.238; 3.P.228.239; 3.P.228.154;3.P.228.157; 3.P.228.166; 3.P.228.169; 3.P.228.172; 3.P.228.175;3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229; 3.P.229.230;3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239;3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172;3.P.229.175; 3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229;3.P.230.230; 3.P.230.231; 3.P.230.236; 3.P.230.237; 3.P.230.238;3.P.230.239; 3.P.230.154; 3.P.230.157; 3.P.230.166; 3.P.230.169;3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244; 3.P.231.228;3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237;3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166;3.P.231.169; 3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244;3.P.236.228; 3.P.236.229; 3.P.236.230; 3.P.236.231; 3.P.236.236;3.P.236.237; 3.P.236.238; 3.P.236.239; 3.P.236.154; 3.P.236.157;3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175; 3.P.236.240;3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231;3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154;3.P.237.157; 3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175;3.P.237.240; 3.P.237.244; 3.P.238.228; 3.P.238.229; 3.P.238.230;3.P.238.231; 3.P.238.236; 3.P.238.237; 3.P.238.238; 3.P.238.239;3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169; 3.P.238.172;3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229;3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238;3.P.239.239; 3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169;3.P.239.172; 3.P.239.175; 3.P.239.240; 3.P.239.244; 3.P.154.228;3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236; 3.P.154.237;3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166;3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244;3.P.157.228; 3.P.157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236;3.P.157.237; 3.P.157.238; 3.P.157.239; 3.P.157.154; 3.P.157.157;3.P.157.166; 3.P.157.169; 3.P.157.172; 3.P.157.175; 3.P.157.240;3.P.157.244; 3.P.166.228; 3.P.166.229; 3.P.166.230; 3.P.166.231;3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154;3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175;3.P.166.240; 3.P.166.244; 3.P.169.228; 3.P.169.229; 3.P.169.230;3.P.169.231; 3.P.169.236; 3.P.169.237; 3.P.169.238; 3.P.169.239;3.P.169.154; 3.P.169.157; 3.P.169.166; 3.P.169.169; 3.P.169.172;3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228; 3.P.172.229;3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238;3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169;3.P.172.172; 3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228;3.P.175.229; 3.P.175.230; 3.P.175.231; 3.P.175.236; 3.P.175.237;3.P.175.238; 3.P.175.239; 3.P.175.154; 3.P.175.157; 3.P.175.166;3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240; 3.P.175.244;3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236;3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157;3.P.240.166; 3.P.240.169; 3.P.240.172; 3.P.240.175; 3.P.240.240;3.P.240.244; 3.P.244.228; 3.P.244.229; 3.P.244.230; 3.P.244.231;3.P.244.236; 3.P.244.237; 3.P.244.238; 3.P.244.239; 3.P.244.154;3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172; 3.P.244.175;3.P.244.240; 3.P.244.244; Prodrugs of 3.U 3.U.228.228; 3.U.228.229;3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237; 3.U.228.238;3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169;3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228;3.U.229.229; 3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237;3.U.229.238; 3.U.229.239; 3.U.229.154; 3.U.229.157; 3.U.229.166;3.U.229.169; 3.U.229.172; 3.U.229.175; 3.U.229.240; 3.U.229.244;3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231; 3.U.230.236;3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157;3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240;3.U.230.244; 3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231;3.U.231.236; 3.U.231.237; 3.U.231.238; 3.U.231.239; 3.U.231.154;3.U.231.157; 3.U.231.166; 3.U.231.169; 3.U.231.172; 3.U.231.175;3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229; 3.U.236.230;3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239;3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172;3.U.236.175; 3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229;3.U.237.230; 3.U.237.231; 3.U.237.236; 3.U.237.237; 3.U.237.238;3.U.237.239; 3.U.237.154; 3.U.237.157; 3.U.237.166; 3.U.237.169;3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244; 3.U.238.228;3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237;3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166;3.U.238.169; 3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244;3.U.239.228; 3.U.239.229; 3.U.239.230; 3.U.239.231; 3.U.239.236;3.U.239.237; 3.U.239.238; 3.U.239.239; 3.U.239.154; 3.U.239.157;3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175; 3.U.239.240;3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231;3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154;3.U.154.157; 3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175;3.U.154.240; 3.U.154.244; 3.U.157.228; 3.U.157.229; 3.U.157.230;3.U.157.231; 3.U.157.236; 3.U.157.237; 3.U.157.238; 3.U.157.239;3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169; 3.U.157.172;3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229;3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238;3.U.166.239; 3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169;3.U.166.172; 3.U.166.175; 3.U.166.240; 3.U.166.244; 3.U.169.228;3.U.169.229; 3.U.169.230; 3.U.169.231; 3.U.169.236; 3.U.169.237;3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157; 3.U.169.166;3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244;3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236;3.U.172.237; 3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157;3.U.172.166; 3.U.172.169; 3.U.172.172; 3.U.172.175; 3.U.172.240;3.U.172.244; 3.U.175.228; 3.U.175.229; 3.U.175.230; 3.U.175.231;3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239; 3.U.175.154;3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175;3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230;3.U.240.231; 3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239;3.U.240.154; 3.U.240.157; 3.U.240.166; 3.U.240.169; 3.U.240.172;3.U.240.175; 3.U.240.240; 3.U.240.244; 3.U.244.228; 3.U.244.229;3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237; 3.U.244.238;3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169;3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244; Prodrugs of 3.W3.W.228.228; 3.W.228.229; 3.W.228.230; 3.W.228.231; 3.W.228.236;3.W.228.237; 3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W.228.157;3.W.228.166; 3.W.228.169; 3.W.228.172; 3.W.228.175; 3.W.228.240;3.W.228.244; 3.W.229.228; 3.W.229.229; 3.W.229.230; 3.W.229.231;3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239; 3.W.229.154;3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175;3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230;3.W.230.231; 3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239;3.W.230.154; 3.W.230.157; 3.W.230.166; 3.W.230.169; 3.W.230.172;3.W.230.175; 3.W.230.240; 3.W.230.244; 3.W.231.228; 3.W.231.229;3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237; 3.W.231.238;3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169;3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228;3.W.236.229; 3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237;3.W.236.238; 3.W.236.239; 3.W.236.154; 3.W.236.157; 3.W.236.166;3.W.236.169; 3.W.236.172; 3.W.236.175; 3.W.236.240; 3.W.236.244;3.W.237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231; 3.W.237.236;3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157;3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240;3.W.237.244; 3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231;3.W.238.236; 3.W.238.237; 3.W.238.238; 3.W.238.239; 3.W.238.154;3.W.238.157; 3.W.238.166; 3.W.238.169; 3.W.238.172; 3.W.238.175;3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229; 3.W.239.230;3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239;3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172;3.W.239.175; 3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229;3.W.154.230; 3.W.154.231; 3.W.154.236; 3.W.154.237; 3.W.154.238;3.W.154.239; 3.W.154.154; 3.W.154.157; 3.W.154.166; 3.W.154.169;3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244; 3.W.157.228;3.W.157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237;3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166;3.W.157.169; 3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244;3.W.166.228; 3.W.166.229; 3.W.166.230; 3.W.166.231; 3.W.166.236;3.W.166.237; 3.W.166.238; 3.W.166.239; 3.W.166.154; 3.W.166.157;3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175; 3.W.166.240;3.W.166.244; 3.W.169.228; 3.W.169.229; 3.W.169.230; 3.W.169.231;3.W.169.236; 3.W.169.237; 3.W.169.238; 3.W.169.239; 3.W.169.154;3.W.169.157; 3.W.169.166; 3.W.169.169; 3.W.169.172; 3.W.169.175;3.W.169.240; 3.W.169.244; 3.W.172.228; 3.W.172.229; 3.W.172.230;3.W.172.231; 3.W.172.236; 3.W.172.237; 3.W.172.238; 3.W.172.239;3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169; 3.W.172.172;3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229;3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238;3.W.175.239; 3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169;3.W.175.172; 3.W.175.175; 3.W.175.240; 3.W.175.244; 3.W.240.228;3.W.240.229; 3.W.240.230; 3.W.240.231; 3.W.240.236; 3.W.240.237;3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157; 3.W.240.166;3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244;3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236;3.W.244.237; 3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157;3.W.244.166; 3.W.244.169; 3.W.244.172; 3.W.244.175; 3.W.244.240;3.W.244.244; Prodrugs of 3.Y 3.Y.228.228; 3.Y.228.229; 3.Y.228.230;3.Y.228.231; 3.Y.228.236; 3.Y.228.237; 3.Y.228.238; 3.Y.228.239;3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169; 3.Y.228.172;3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229;3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238;3.Y.229.239; 3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169;3.Y.229.172; 3.Y.229.175; 3.Y.229.240; 3.Y.229.244; 3.Y.230.228;3.Y.230.229; 3.Y.230.230; 3.Y.230.231; 3.Y.230.236; 3.Y.230.237;3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157; 3.Y.230.166;3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244;3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236;3.Y.231.237; 3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157;3.Y.231.166; 3.Y.231.169; 3.Y.231.172; 3.Y.231.175; 3.Y.231.240;3.Y.231.244; 3.Y.236.228; 3.Y.236.229; 3.Y.236.230; 3.Y.236.231;3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239; 3.Y.236.154;3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175;3.Y.236.240; 3.Y.236.244; 3.Y.237.228; 3.Y.237.229; 3.Y.237.230;3.Y.237.231; 3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239;3.Y.237.154; 3.Y.237.157; 3.Y.237.166; 3.Y.237.169; 3.Y.237.172;3.Y.237.175; 3.Y.237.240; 3.Y.237.244; 3.Y.238.228; 3.Y.238.229;3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237; 3.Y.238.238;3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169;3.Y.238.172; 3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228;3.Y.239.229; 3.Y.239.230; 3.Y.239.231; 3.Y.239.236; 3.Y.239.237;3.Y.239.238; 3.Y.239.239; 3.Y.239.154; 3.Y.239.157; 3.Y.239.166;3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240; 3.Y.239.244;3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236;3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157;3.Y.154.166; 3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240;3.Y.154.244; 3.Y.157.228; 3.Y.157.229; 3.Y.157.230; 3.Y.157.231;3.Y.157.236; 3.Y.157.237; 3.Y.157.238; 3.Y.157.239; 3.Y.157.154;3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172; 3.Y.157.175;3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230;3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239;3.Y.166.154; 3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172;3.Y.166.175; 3.Y.166.240; 3.Y.166.244; 3.Y.169.228; 3.Y.169.229;3.Y.169.230; 3.Y.169.231; 3.Y.169.236; 3.Y.169.237; 3.Y.169.238;3.Y.169.239; 3.Y.169.154; 3.Y.169.157; 3.Y.169.166; 3.Y.169.169;3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228;3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237;3.Y.172.238; 3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166;3.Y.172.169; 3.Y.172.172; 3.Y.172.175; 3.Y.172.240; 3.Y.172.244;3.Y.175.228; 3.Y.175.229; 3.Y.175.230; 3.Y.175.231; 3.Y.175.236;3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154; 3.Y.175.157;3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240;3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231;3.Y.240.236; 3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154;3.Y.240.157; 3.Y.240.166; 3.Y.240.169; 3.Y.240.172; 3.Y.240.175;3.Y.240.240; 3.Y.240.244; 3.Y.244.228; 3.Y.244.229; 3.Y.244.230;3.Y.244.231; 3.Y.244.236; 3.Y.244.237; 3.Y.244.238; 3.Y.244.239;3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172;3.Y.244.175; 3.Y.244.240; 3.Y.244.244; Prodrugs of 4.B 4.B.228.228;4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237;4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166;4.B.228.169; 4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244;4.B.229.228; 4.B.229.229; 4.B.229.230; 4.B.229.231; 4.B.229.236;4.B.229.237; 4.B.229.238; 4.B.229.239; 4.B.229.154; 4.B.229.157;4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175; 4.B.229.240;4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231;4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154;4.B.230.157; 4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175;4.B.230.240; 4.B.230.244; 4.B.231.228; 4.B.231.229; 4.B.231.230;4.B.231.231; 4.B.231.236; 4.B.231.237; 4.B.231.238; 4.B.231.239;4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169; 4.B.231.172;4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229;4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238;4.B.236.239; 4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169;4.B.236.172; 4.B.236.175; 4.B.236.240; 4.B.236.244; 4.B.237.228;4.B.237.229; 4.B.237.230; 4.B.237.231; 4.B.237.236; 4.B.237.237;4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157; 4.B.237.166;4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244;4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231; 4.B.238.236;4.B.238.237; 4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157;4.B.238.166; 4.B.238.169; 4.B.238.172; 4.B.238.175; 4.B.238.240;4.B.238.244; 4.B.239.228; 4.B.239.229; 4.B.239.230; 4.B.239.231;4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239; 4.B.239.154;4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175;4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230;4.B.154.231; 4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239;4.B.154.154; 4.B.154.157; 4.B.154.166; 4.B.154.169; 4.B.154.172;4.B.154.175; 4.B.154.240; 4.B.154.244; 4.B.157.228; 4.B.157.229;4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237; 4.B.157.238;4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169;4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228;4.B.166.229; 4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237;4.B.166.238; 4.B.166.239; 4.B.166.154; 4.B.166.157; 4.B.166.166;4.B.166.169; 4.B.166.172; 4.B.166.175; 4.B.166.240; 4.B.166.244;4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236;4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157;4.B.169.166; 4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B.169.240;4.B.169.244; 4.B.172.228; 4.B.172.229; 4.B.172.230; 4.B.172.231;4.B.172.236; 4.B.172.237; 4.B.172.238; 4.B.172.239; 4.B.172.154;4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172; 4.B.172.175;4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230;4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239;4.B.175.154; 4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172;4.B.175.175; 4.B.175.240; 4.B.175.244; 4.B.240.228; 4.B.240.229;4.B.240.230; 4.B.240.231; 4.B.240.236; 4.B.240.237; 4.B.240.238;4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166; 4.B.240.169;4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228;4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237;4.B.244.238; 4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166;4.B.244.169; 4.B.244.172; 4.B.244.175; 4.B.244.240; 4.B.244.244;Prodrugs of 4.D 4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231;4.D.228.236; 4.D.228.237; 4.D.228.238; 4.D.228.239; 4.D.228.154;4.D.228.157; 4.D.228.166; 4.D.228.169; 4.D.228.172; 4.D.228.175;4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229; 4.D.229.230;4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239;4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172;4.D.229.175; 4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229;4.D.230.230; 4.D.230.231; 4.D.230.236; 4.D.230.237; 4.D.230.238;4.D.230.239; 4.D.230.154; 4.D.230.157; 4.D.230.166; 4.D.230.169;4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244; 4.D.231.228;4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237;4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166;4.D.231.169; 4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244;4.D.236.228; 4.D.236.229; 4.D.236.230; 4.D.236.231; 4.D.236.236;4.D.236.237; 4.D.236.238; 4.D.236.239; 4.D.236.154; 4.D.236.157;4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175; 4.D.236.240;4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231;4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154;4.D.237.157; 4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175;4.D.237.240; 4.D.237.244; 4.D.238.228; 4.D.238.229; 4.D.238.230;4.D.238.231; 4.D.238.236; 4.D.238.237; 4.D.238.238; 4.D.238.239;4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169; 4.D.238.172;4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229;4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238;4.D.239.239; 4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169;4.D.239.172; 4.D.239.175; 4.D.239.240; 4.D.239.244; 4.D.154.228;4.D.154.229; 4.D.154.230; 4.D.154.231; 4.D.154.236; 4.D.154.237;4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157; 4.D.154.166;4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244;4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236;4.D.157.237; 4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157;4.D.157.166; 4.D.157.169; 4.D.157.172; 4.D.157.175; 4.D.157.240;4.D.157.244; 4.D.166.228; 4.D.166.229; 4.D.166.230; 4.D.166.231;4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239; 4.D.166.154;4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175;4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230;4.D.169.231; 4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239;4.D.169.154; 4.D.169.157; 4.D.169.166; 4.D.169.169; 4.D.169.172;4.D.169.175; 4.D.169.240; 4.D.169.244; 4.D.172.228; 4.D.172.229;4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237; 4.D.172.238;4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169;4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228;4.D.175.229; 4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237;4.D.175.238; 4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166;4.D.175.169; 4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244;4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236;4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157;4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240;4.D.240.244; 4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231;4.D.244.236; 4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154;4.D.244.157; 4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175;4.D.244.240; 4.D.244.244; Prodrugs of 4.E 4.E.228.228; 4.E.228.229;4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238;4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169;4.E.228.172; 4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228;4.E.229.229; 4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237;4.E.229.238; 4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166;4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244;4.E.230.228; 4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236;4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157;4.E.230.166; 4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240;4.E.230.244; 4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231;4.E.231.236; 4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154;4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175;4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230;4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239;4.E.236.154; 4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172;4.E.236.175; 4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229;4.E.237.230; 4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238;4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169;4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228;4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237;4.E.238.238; 4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166;4.E.238.169; 4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244;4.E.239.228; 4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236;4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157;4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240;4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231;4.E.154.236; 4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154;4.E.154.157; 4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175;4.E.154.240; 4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230;4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239;4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172;4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229;4.E.166.230; 4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238;4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169;4.E.166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228;4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237;4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166;4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244;4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236;4.E.172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157;4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240;4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231;4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154;4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175;4.E.175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230;4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239;4.E.240.154; 4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172;4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229;4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238;4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169;4.E.244.172; 4.E.244.175; 4.E.244.240; 4.E.244.244; Prodrugs of 4.G4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236;4.G.228.237; 4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157;4.G.228.166; 4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240;4.G.228.244; 4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231;4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154;4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175;4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230;4.G.230.231; 4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239;4.G.230.154; 4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172;4.G.230.175; 4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229;4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238;4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169;4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228;4.G.236.229; 4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237;4.G.236.238; 4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166;4.G.236.169; 4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244;4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236;4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157;4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240;4.G.237.244; 4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231;4.G.238.236; 4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154;4.G.238.157; 4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175;4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230;4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239;4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172;4.G.239.175; 4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229;4.G.154.230; 4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238;4.G.154.239; 4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169;4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228;4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237;4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166;4.G.157.169; 4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244;4.G.166.228; 4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236;4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157;4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240;4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231;4.G.169.236; 4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154;4.G.169.157; 4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175;4.G.169.240; 4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230;4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239;4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172;4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229;4.G.175.230; 4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238;4.G.175.239; 4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169;4.G.175.172; 4.G.175.175; 4.G.175.240; 4.G.175.244; 4.G.240.228;4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237;4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166;4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244;4.G.244.228; 4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236;4.G.244.237; 4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157;4.G.244.166; 4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240;4.G.244.244; Prodrugs of 4.I 4.I.228.228; 4.I.228.229; 4.I.228.230;4.I.228.231; 4.I.228.236; 4.I.228.237; 4.I.228.238; 4.I.228.239;4.I.228.154; 4.I.228.157; 4.I.228.166; 4.I.228.169; 4.I.228.172;4.I.228.175; 4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229;4.I.229.230; 4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238;4.I.229.239; 4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169;4.I.229.172; 4.I.229.175; 4.I.229.240; 4.I.229.244; 4.I.230.228;4.I.230.229; 4.I.230.230; 4.I.230.231; 4.I.230.236; 4.I.230.237;4.I.230.238; 4.I.230.239; 4.I.230.154; 4.I.230.157; 4.I.230.166;4.I.230.169; 4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244;4.I.231.228; 4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236;4.I.231.237; 4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157;4.I.231.166; 4.I.231.169; 4.I.231.172; 4.I.231.175; 4.I.231.240;4.I.231.244; 4.I.236.228; 4.I.236.229; 4.I.236.230; 4.I.236.231;4.I.236.236; 4.I.236.237; 4.I.236.238; 4.I.236.239; 4.I.236.154;4.I.236.157; 4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175;4.I.236.240; 4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230;4.I.237.231; 4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239;4.I.237.154; 4.I.237.157; 4.I.237.166; 4.I.237.169; 4.I.237.172;4.I.237.175; 4.I.237.240; 4.I.237.244; 4.I.238.228; 4.I.238.229;4.I.238.230; 4.I.238.231; 4.I.238.236; 4.I.238.237; 4.I.238.238;4.I.238.239; 4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169;4.I.238.172; 4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228;4.I.239.229; 4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237;4.I.239.238; 4.I.239.239; 4.I.239.154; 4.I.239.157; 4.I.239.166;4.I.239.169; 4.I.239.172; 4.I.239.175; 4.I.239.240; 4.I.239.244;4.I.154.228; 4.I.154.229; 4.I.154.230; 4.I.154.231; 4.I.154.236;4.I.154.237; 4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157;4.I.154.166; 4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240;4.I.154.244; 4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231;4.I.157.236; 4.I.157.237; 4.I.157.238; 4.I.157.239; 4.I.157.154;4.I.157.157; 4.I.157.166; 4.I.157.169; 4.I.157.172; 4.I.157.175;4.I.157.240; 4.I.157.244; 4.I.166.228; 4.I.166.229; 4.I.166.230;4.I.166.231; 4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239;4.I.166.154; 4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172;4.I.166.175; 4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229;4.I.169.230; 4.I.169.231; 4.I.169.236; 4.I.169.237; 4.I.169.238;4.I.169.239; 4.I.169.154; 4.I.169.157; 4.I.169.166; 4.I.169.169;4.I.169.172; 4.I.169.175; 4.I.169.240; 4.I.169.244; 4.I.172.228;4.I.172.229; 4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237;4.I.172.238; 4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166;4.I.172.169; 4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244;4.I.175.228; 4.I.175.229; 4.I.175.230; 4.I.175.231; 4.I.175.236;4.I.175.237; 4.I.175.238; 4.I.175.239; 4.I.175.154; 4.I.175.157;4.I.175.166; 4.I.175.169; 4.I.175.172; 4.I.175.175; 4.I.175.240;4.I.175.244; 4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231;4.I.240.236; 4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154;4.I.240.157; 4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175;4.I.240.240; 4.I.240.244; 4.I.244.228; 4.I.244.229; 4.I.244.230;4.I.244.231; 4.I.244.236; 4.I.244.237; 4.I.244.238; 4.I.244.239;4.I.244.154; 4.I.244.157; 4.I.244.166; 4.I.244.169; 4.I.244.172;4.I.244.175; 4.I.244.240; 4.I.244.244; Prodrugs of 4.J 4.J.228.228;4.J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237;4.J.228.238; 4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166;4.J.228.169; 4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244;4.J.229.228; 4.J.229.229; 4.J.229.230; 4.J.229.231; 4.J.229.236;4.J.229.237; 4.J.229.238; 4.J.229.239; 4.J.229.154; 4.J.229.157;4.J.229.166; 4.J.229.169; 4.J.229.172; 4.J.229.175; 4.J.229.240;4.J.229.244; 4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231;4.J.230.236; 4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154;4.J.230.157; 4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175;4.J.230.240; 4.J.230.244; 4.J.231.228; 4.J.231.229; 4.J.231.230;4.J.231.231; 4.J.231.236; 4.J.231.237; 4.J.231.238; 4.J.231.239;4.J.231.154; 4.J.231.157; 4.J.231.166; 4.J.231.169; 4.J.231.172;4.J.231.175; 4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229;4.J.236.230; 4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238;4.J.236.239; 4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169;4.J.236.172; 4.J.236.175; 4.J.236.240; 4.J.236.244; 4.J.237.228;4.J.237.229; 4.J.237.230; 4.J.237.231; 4.J.237.236; 4.J.237.237;4.J.237.238; 4.J.237.239; 4.J.237.154; 4.J.237.157; 4.J.237.166;4.J.237.169; 4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244;4.J.238.228; 4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236;4.J.238.237; 4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157;4.J.238.166; 4.J.238.169; 4.J.238.172; 4.J.238.175; 4.J.238.240;4.J.238.244; 4.J.239.228; 4.J.239.229; 4.J.239.230; 4.J.239.231;4.J.239.236; 4.J.239.237; 4.J.239.238; 4.J.239.239; 4.J.239.154;4.J.239.157; 4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175;4.J.239.240; 4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230;4.J.154.231; 4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239;4.J.154.154; 4.J.154.157; 4.J.154.166; 4.J.154.169; 4.J.154.172;4.J.154.175; 4.J.154.240; 4.J.154.244; 4.J.157.228; 4.J.157.229;4.J.157.230; 4.J.157.231; 4.J.157.236; 4.J.157.237; 4.J.157.238;4.J.157.239; 4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169;4.J.157.172; 4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228;4.J.166.229; 4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237;4.J.166.238; 4.J.166.239; 4.J.166.154; 4.J.166.157; 4.J.166.166;4.J.166.169; 4.J.166.172; 4.J.166.175; 4.J.166.240; 4.J.166.244;4.J.169.228; 4.J.169.229; 4.J.169.230; 4.J.169.231; 4.J.169.236;4.J.169.237; 4.J.169.238; 4.J.169.239; 4.J.169.154; 4.J.169.157;4.J.169.166; 4.J.169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240;4.J.169.244; 4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231;4.J.172.236; 4.J.172.237; 4.J.172.238; 4.J.172.239; 4.J.172.154;4.J.172.157; 4.J.172.166; 4.J.172.169; 4.J.172.172; 4.J.172.175;4.J.172.240; 4.J.172.244; 4.J.175.228; 4.J.175.229; 4.J.175.230;4.J.175.231; 4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239;4.J.175.154; 4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172;4.J.175.175; 4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229;4.J.240.230; 4.J.240.231; 4.J.240.236; 4.J.240.237; 4.J.240.238;4.J.240.239; 4.J.240.154; 4.J.240.157; 4.J.240.166; 4.J.240.169;4.J.240.172; 4.J.240.175; 4.J.240.240; 4.J.240.244; 4.J.244.228;4.J.244.229; 4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237;4.J.244.238; 4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166;4.J.244.169; 4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244;Prodrugs of 4.L 4.L.228.228; 4.L.228.229; 4.L.228.230; 4.L.228.231;4.L.228.236; 4.L.228.237; 4.L.228.238; 4.L.228.239; 4.L.228.154;4.L.228.157; 4.L.228.166; 4.L.228.169; 4.L.228.172; 4.L.228.175;4.L.228.240; 4.L.228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230;4.L.229.231; 4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239;4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172;4.L.229.175; 4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229;4.L.230.230; 4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238;4.L.230.239; 4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169;4.L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228;4.L.231.229; 4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237;4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166;4.L.231.169; 4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244;4.L.236.228; 4.L.236.229; 4.L.236.230; 4.L.236.231; 4.L.236.236;4.L.236.237; 4.L.236.238; 4.L.236.239; 4.L.236.154; 4.L.236.157;4.L.236.166; 4.L.236.169; 4.L.236.172; 4.L.236.175; 4.L.236.240;4.L.236.244; 4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231;4.L.237.236; 4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154;4.L.237.157; 4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175;4.L.237.240; 4.L.237.244; 4.L.238.228; 4.L.238.229; 4.L.238.230;4.L.238.231; 4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239;4.L.238.154; 4.L.238.157; 4.L.238.166; 4.L.238.169; 4.L.238.172;4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229;4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238;4.L.239.239; 4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169;4.L.239.172; 4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L.154.228;4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237;4.L.154.238; 4.L.154.239; 4.L.154.154; 4.L.154.157; 4.L.154.166;4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244;4.L.157.228; 4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236;4.L.157.237; 4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157;4.L.157.166; 4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240;4.L.157.244; 4.L.166.228; 4.L.166.229; 4.L.166.230; 4.L.166.231;4.L.166.236; 4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154;4.L.166.157; 4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175;4.L.166.240; 4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230;4.L.169.231; 4.L.169.236; 4.L.169.237; 4.L.169.238; 4.L.169.239;4.L.169.154; 4.L.169.157; 4.L.169.166; 4.L.169.169; 4.L.169.172;4.L.169.175; 4.L.169.240; 4.L.169.244; 4.L.172.228; 4.L.172.229;4.L.172.230; 4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238;4.L.172.239; 4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169;4.L.172.172; 4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228;4.L.175.229; 4.L.175.230; 4.L.175.231; 4.L.175.236; 4.L.175.237;4.L.175.238; 4.L.175.239; 4.L.175.154; 4.L.175.157; 4.L.175.166;4.L.175.169; 4.L.175.172; 4.L.175.175; 4.L.175.240; 4.L.175.244;4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236;4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157;4.L.240.166; 4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240;4.L.240.244; 4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231;4.L.244.236; 4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154;4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175;4.L.244.240; 4.L.244.244; Prodrugs of 4.O 4.O.228.228; 4.O.228.229;4.O.228.230; 4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238;4.O.228.239; 4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169;4.O.228.172; 4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228;4.O.229.229; 4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237;4.O.229.238; 4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166;4.O.229.169; 4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244;4.O.230.228; 4.O.230.229; 4.O.230.230; 4.O.230.231; 4.O.230.236;4.O.230.237; 4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O.230.157;4.O.230.166; 4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.230.240;4.O.230.244; 4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231;4.O.231.236; 4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154;4.O.231.157; 4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175;4.O.231.240; 4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230;4.O.236.231; 4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239;4.O.236.154; 4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172;4.O.236.175; 4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229;4.O.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238;4.O.237.239; 4.O.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169;4.O.237.172; 4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228;4.O.238.229; 4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237;4.O.238.238; 4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166;4.O.238.169; 4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244;4.O.239.228; 4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236;4.O.239.237; 4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157;4.O.239.166; 4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240;4.O.239.244; 4.O.154.228; 4.O.154.229; 4.O.154.230; 4.O.154.231;4.O.154.236; 4.O.154.237; 4.O.154.238; 4.O.154.239; 4.O.154.154;4.O.154.157; 4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175;4.O.154.240; 4.O.154.244; 4.O.157.228; 4.O.157.229; 4.O.157.230;4.O.157.231; 4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239;4.O.157.154; 4.O.157.157; 4.O.157.166; 4.O.157.169; 4.O.157.172;4.O.157.175; 4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229;4.O.166.230; 4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238;4.O.166.239; 4.O.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169;4.O.166.172; 4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228;4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237;4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166;4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244;4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236;4.O.172.237; 4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157;4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240;4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231;4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154;4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175;4.O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230;4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239;4.O.240.154; 4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172;4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229;4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238;4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169;4.O.244.172; 4.O.244.175; 4.O.244.240; 4.O.244.244; Prodrugs of 4.P4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236;4.P.228.237; 4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157;4.P.228.166; 4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240;4.P.228.244; 4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231;4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154;4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175;4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230;4.P.230.231; 4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239;4.P.230.154; 4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172;4.P.230.175; 4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229;4.P.231.230; 4.P.231.231; 4.P.231.236; 4.P.231.237; 4.P.231.238;4.P.231.239; 4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169;4.P.231.172; 4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228;4.P.236.229; 4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237;4.P.236.238; 4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166;4.P.236.169; 4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244;4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236;4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157;4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240;4.P.237.244; 4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231;4.P.238.236; 4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154;4.P.238.157; 4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175;4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230;4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239;4.P.239.154; 4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172;4.P.239.175; 4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229;4.P.154.230; 4.P.154.231; 4.P.154.236; 4.P.154.237; 4.P.154.238;4.P.154.239; 4.P.154.154; 4.P.154.157; 4.P.154.166; 4.P.154.169;4.P.154.172; 4.P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228;4.P.157.229; 4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237;4.P.157.238; 4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166;4.P.157.169; 4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244;4.P.166.228; 4.P.166.229; 4.P.166.230; 4.P.166.231; 4.P.166.236;4.P.166.237; 4.P.166.238; 4.P.166.239; 4.P.166.154; 4.P.166.157;4.P.166.166; 4.P.166.169; 4.P.166.172; 4.P.166.175; 4.P.166.240;4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231;4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154;4.P.169.157; 4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175;4.P.169.240; 4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230;4.P.172.231; 4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239;4.P.172.154; 4.P.172.157; 4.P.172.166; 4.P.172.169; 4.P.172.172;4.P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229;4.P.175.230; 4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238;4.P.175.239; 4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169;4.P.175.172; 4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228;4.P.240.229; 4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237;4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166;4.P.240.169; 4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244;4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236;4.P.244.237; 4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157;4.P.244.166; 4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240;4.P.244.244; Prodrugs of 4.U 4.U.228.228; 4.U.228.229; 4.U.228.230;4.U.228.231; 4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239;4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172;4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229;4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238;4.U.229.239; 4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169;4.U.229.172; 4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228;4.U.230.229; 4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237;4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166;4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244;4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236;4.U.231.237; 4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157;4.U.231.166; 4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240;4.U.231.244; 4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231;4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154;4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175;4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230;4.U.237.231; 4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239;4.U.237.154; 4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172;4.U.237.175; 4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229;4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238;4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169;4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228;4.U.239.229; 4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237;4.U.239.238; 4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166;4.U.239.169; 4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244;4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236;4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157;4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240;4.U.154.244; 4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231;4.U.157.236; 4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154;4.U.157.157; 4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175;4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230;4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239;4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172;4.U.166.175; 4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229;4.U.169.230; 4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238;4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169;4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228;4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237;4.U.172.238; 4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166;4.U.172.169; 4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244;4.U.175.228; 4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236;4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157;4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240;4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231;4.U.240.236; 4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154;4.U.240.157; 4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175;4.U.240.240; 4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230;4.U.244.231; 4.U.244.236; 4.U.244.237; 4.U.244.238; 4.U.244.239;4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172;4.U.244.175; 4.U.244.240; 4.U.244.244; Prodrugs of 4.W 4.W.228.228;4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237;4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166;4.W.228.169; 4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244;4.W.229.228; 4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236;4.W.229.237; 4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157;4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240;4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231;4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154;4.W.230.157; 4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175;4.W.230.240; 4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230;4.W.231.231; 4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239;4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172;4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229;4.W.236.230; 4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238;4.W.236.239; 4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169;4.W.236.172; 4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228;4.W.237.229; 4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237;4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166;4.W.237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244;4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236;4.W.238.237; 4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157;4.W.238.166; 4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240;4.W.238.244; 4.W.239.228; 4.W.239.229; 4.W.239.230; 4.W.239.231;4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154;4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175;4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230;4.W.154.231; 4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239;4.W.154.154; 4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172;4.W.154.175; 4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W.157.229;4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238;4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169;4.W.157.172; 4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228;4.W.166.229; 4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237;4.W.166.238; 4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166;4.W.166.169; 4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244;4.W.169.228; 4.W.169.229; 4.W.169.230; 4.W.169.231; 4.W.169.236;4.W.169.237; 4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157;4.W.169.166; 4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240;4.W.169.244; 4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231;4.W.172.236; 4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154;4.W.172.157; 4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175;4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230;4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239;4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172;4.W.175.175; 4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229;4.W.240.230; 4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238;4.W.240.239; 4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169;4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228;4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237;4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166;4.W.244.169; 4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;Prodrugs of 4.Y 4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231;4.Y.228.236; 4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154;4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175;4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230;4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239;4.Y.229.154; 4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172;4.Y.229.175; 4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229;4.Y.230.230; 4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238;4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169;4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228;4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237;4.Y.231.238; 4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166;4.Y.231.169; 4.Y.231.172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244;4.Y.236.228; 4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236;4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157;4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240;4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231;4.Y.237.236; 4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154;4.Y.237.157; 4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175;4.Y.237.240; 4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230;4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239;4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172;4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229;4.Y.239.230; 4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238;4.Y.239.239; 4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169;4.Y.239.172; 4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228;4.Y.154.229; 4.Y.154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237;4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166;4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244;4.Y.157.228; 4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236;4.Y.157.237; 4.Y.157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157;4.Y.157.166; 4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240;4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231;4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154;4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175;4.Y.166.240; 4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230;4.Y.169.231; 4.Y.169.236; 4.Y.169.237; 4.Y.169.238; 4.Y.169.239;4.Y.169.154; 4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172;4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229;4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238;4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169;4.Y.172.172; 4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228;4.Y.175.229; 4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237;4.Y.175.238; 4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166;4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244;4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236;4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157;4.Y.240.166; 4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240;4.Y.240.244; 4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231;4.Y.244.236; 4.Y.244.237; 4.Y.244.238; 4.Y.244.239; 4.Y.244.154;4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175;4.Y.244.240; 4.Y.244.244; Prodrugs of 5.B 5.B.228.228; 5.B.228.229;5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238;5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169;5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228;5.B.229.229; 5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237;5.B.229.238; 5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166;5.B.229.169; 5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244;5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236;5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157;5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240;5.B.230.244; 5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231;5.B.231.236; 5.B.231.237; 5.B.231.238; 5.B.231.239; 5.B.231.154;5.B.231.157; 5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175;5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230;5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239;5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172;5.B.236.175; 5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229;5.B.237.230; 5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238;5.B.237.239; 5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169;5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228;5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237;5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166;5.B.238.169; 5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244;5.B.239.228; 5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236;5.B.239.237; 5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157;5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240;5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231;5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154;5.B.154.157; 5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175;5.B.154.240; 5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230;5.B.157.231; 5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239;5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172;5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229;5.B.166.230; 5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238;5.B.166.239; 5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169;5.B.166.172; 5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228;5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237;5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166;5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244;5.B.172.228; 5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236;5.B.172.237; 5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157;5.B.172.166; 5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240;5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231;5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154;5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175;5.B.175.240; 5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230;5.B.240.231; 5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239;5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172;5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229;5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238;5.B.244.239; 5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169;5.B.244.172; 5.B.244.175; 5.B.244.240; 5.B.244.244; Prodrugs of 5.D5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236;5.D.228.237; 5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157;5.D.228.166; 5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240;5.D.228.244; 5.D.229.228; 5.D.229.229; 5.D.229.230; 5.D.229.231;5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154;5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175;5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230;5.D.230.231; 5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239;5.D.230.154; 5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172;5.D.230.175; 5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229;5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238;5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169;5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228;5.D.236.229; 5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237;5.D.236.238; 5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166;5.D.236.169; 5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244;5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236;5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157;5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240;5.D.237.244; 5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231;5.D.238.236; 5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154;5.D.238.157; 5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175;5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230;5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239;5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172;5.D.239.175; 5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229;5.D.154.230; 5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238;5.D.154.239; 5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169;5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228;5.D.157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237;5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166;5.D.157.169; 5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244;5.D.166.228; 5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236;5.D.166.237; 5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157;5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240;5.D.166.244; 5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231;5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154;5.D.169.157; 5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175;5.D.169.240; 5.D.169.244; 5.D.172.228; 5.D.172.229; 5.D.172.230;5.D.172.231; 5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239;5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172;5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229;5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238;5.D.175.239; 5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169;5.D.175.172; 5.D.175.175; 5.D.175.240; 5.D.175.244; 5.D.240.228;5.D.240.229; 5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237;5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166;5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244;5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236;5.D.244.237; 5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157;5.D.244.166; 5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240;5.D.244.244; Prodrugs of 5.E 5.E.228.228; 5.E.228.229; 5.E.228.230;5.E.228.231; 5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239;5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172;5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229;5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238;5.E.229.239; 5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169;5.E.229.172; 5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228;5.E.230.229; 5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237;5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166;5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244;5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236;5.E.231.237; 5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157;5.E.231.166; 5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240;5.E.231.244; 5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231;5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154;5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175;5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230;5.E.237.231; 5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239;5.E.237.154; 5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172;5.E.237.175; 5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229;5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238;5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169;5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228;5.E.239.229; 5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237;5.E.239.238; 5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166;5.E.239.169; 5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244;5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236;5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157;5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240;5.E.154.244; 5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231;5.E.157.236; 5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154;5.E.157.157; 5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175;5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230;5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239;5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172;5.E.166.175; 5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229;5.E.169.230; 5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238;5.E.169.239; 5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169;5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228;5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237;5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166;5.E.172.169; 5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244;5.E.175.228; 5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236;5.E.175.237; 5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157;5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240;5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231;5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154;5.E.240.157; 5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175;5.E.240.240; 5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230;5.E.244.231; 5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239;5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172;5.E.244.175; 5.E.244.240; 5.E.244.244; Prodrugs of 5.G 5.G.228.228;5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237;5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166;5.G.228.169; 5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244;5.G.229.228; 5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236;5.G.229.237; 5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157;5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240;5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231;5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154;5.G.230.157; 5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175;5.G.230.240; 5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230;5.G.231.231; 5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239;5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172;5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229;5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238;5.G.236.239; 5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169;5.G.236.172; 5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228;5.G.237.229; 5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237;5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166;5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244;5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236;5.G.238.237; 5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157;5.G.238.166; 5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240;5.G.238.244; 5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231;5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154;5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175;5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230;5.G.154.231; 5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239;5.G.154.154; 5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172;5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229;5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238;5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169;5.G.157.172; 5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228;5.G.166.229; 5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237;5.G.166.238; 5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166;5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244;5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236;5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157;5.G.169.166; 5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240;5.G.169.244; 5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231;5.G.172.236; 5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154;5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175;5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230;5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239;5.G.175.154; 5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172;5.G.175.175; 5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229;5.G.240.230; 5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238;5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G.240.166; 5.G.240.169;5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228;5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237;5.G.244.238; 5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166;5.G.244.169; 5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244;Prodrugs of 5.I 5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231;5.I.228.236; 5.I.228.237; 5.I.228.238; 5.I.228.239; 5.I.228.154;5.I.228.157; 5.I.228.166; 5.I.228.169; 5.I.228.172; 5.I.228.175;5.I.228.240; 5.I.228.244; 5.I.229.228; 5.I.229.229; 5.I.229.230;5.I.229.231; 5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239;5.I.229.154; 5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172;5.I.229.175; 5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229;5.I.230.230; 5.I.230.231; 5.I.230.236; 5.I.230.237; 5.I.230.238;5.I.230.239; 5.I.230.154; 5.I.230.157; 5.I.230.166; 5.I.230.169;5.I.230.172; 5.I.230.175; 5.I.230.240; 5.I.230.244; 5.I.231.228;5.I.231.229; 5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237;5.I.231.238; 5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166;5.I.231.169; 5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244;5.I.236.228; 5.I.236.229; 5.I.236.230; 5.I.236.231; 5.I.236.236;5.I.236.237; 5.I.236.238; 5.I.236.239; 5.I.236.154; 5.I.236.157;5.I.236.166; 5.I.236.169; 5.I.236.172; 5.I.236.175; 5.I.236.240;5.I.236.244; 5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231;5.I.237.236; 5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154;5.I.237.157; 5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175;5.I.237.240; 5.I.237.244; 5.I.238.228; 5.I.238.229; 5.I.238.230;5.I.238.231; 5.I.238.236; 5.I.238.237; 5.I.238.238; 5.I.238.239;5.I.238.154; 5.I.238.157; 5.I.238.166; 5.I.238.169; 5.I.238.172;5.I.238.175; 5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229;5.I.239.230; 5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238;5.I.239.239; 5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169;5.I.239.172; 5.I.239.175; 5.I.239.240; 5.I.239.244; 5.I.154.228;5.I.154.229; 5.I.154.230; 5.I.154.231; 5.I.154.236; 5.I.154.237;5.I.154.238; 5.I.154.239; 5.I.154.154; 5.I.154.157; 5.I.154.166;5.I.154.169; 5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244;5.I.157.228; 5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236;5.I.157.237; 5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157;5.I.157.166; 5.I.157.169; 5.I.157.172; 5.I.157.175; 5.I.157.240;5.I.157.244; 5.I.166.228; 5.I.166.229; 5.I.166.230; 5.I.166.231;5.I.166.236; 5.I.166.237; 5.I.166.238; 5.I.166.239; 5.I.166.154;5.I.166.157; 5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175;5.I.166.240; 5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230;5.I.169.231; 5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239;5.I.169.154; 5.I.169.157; 5.I.169.166; 5.I.169.169; 5.I.169.172;5.I.169.175; 5.I.169.240; 5.I.169.244; 5.I.172.228; 5.I.172.229;5.I.172.230; 5.I.172.231; 5.I.172.236; 5.I.172.237; 5.I.172.238;5.I.172.239; 5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169;5.I.172.172; 5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228;5.I.175.229; 5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237;5.I.175.238; 5.I.175.239; 5.I.175.154; 5.I.175.157; 5.I.175.166;5.I.175.169; 5.I.175.172; 5.I.175.175; 5.I.175.240; 5.I.175.244;5.I.240.228; 5.I.240.229; 5.I.240.230; 5.I.240.231; 5.I.240.236;5.I.240.237; 5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157;5.I.240.166; 5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240;5.I.240.244; 5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231;5.I.244.236; 5.I.244.237; 5.I.244.238; 5.I.244.239; 5.I.244.154;5.I.244.157; 5.I.244.166; 5.I.244.169; 5.I.244.172; 5.I.244.175;5.I.244.240; 5.I.244.244; Prodrugs of 5.J 5.J.228.228; 5.J.228.229;5.J.228.230; 5.J.228.231; 5.J.228.236; 5.J.228.237; 5.J.228.238;5.J.228.239; 5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169;5.J.228.172; 5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228;5.J.229.229; 5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237;5.J.229.238; 5.J.229.239; 5.J.229.154; 5.J.229.157; 5.J.229.166;5.J.229.169; 5.J.229.172; 5.J.229.175; 5.J.229.240; 5.J.229.244;5.J.230.228; 5.J.230.229; 5.J.230.230; 5.J.230.231; 5.J.230.236;5.J.230.237; 5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157;5.J.230.166; 5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240;5.J.230.244; 5.J.231.228; 5.J.231.229; 5.J.231.230; 5.J.231.231;5.J.231.236; 5.J.231.237; 5.J.231.238; 5.J.231.239; 5.J.231.154;5.J.231.157; 5.J.231.166; 5.J.231.169; 5.J.231.172; 5.J.231.175;5.J.231.240; 5.J.231.244; 5.J.236.228; 5.J.236.229; 5.J.236.230;5.J.236.231; 5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239;5.J.236.154; 5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172;5.J.236.175; 5.J.236.240; 5.J.236.244; 5.J.237.228; 5.J.237.229;5.J.237.230; 5.J.237.231; 5.J.237.236; 5.J.237.237; 5.J.237.238;5.J.237.239; 5.J.237.154; 5.J.237.157; 5.J.237.166; 5.J.237.169;5.J.237.172; 5.J.237.175; 5.J.237.240; 5.J.237.244; 5.J.238.228;5.J.238.229; 5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237;5.J.238.238; 5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166;5.J.238.169; 5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244;5.J.239.228; 5.J.239.229; 5.J.239.230; 5.J.239.231; 5.J.239.236;5.J.239.237; 5.J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157;5.J.239.166; 5.J.239.169; 5.J.239.172; 5.J.239.175; 5.J.239.240;5.J.239.244; 5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231;5.J.154.236; 5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154;5.J.154.157; 5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175;5.J.154.240; 5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230;5.J.157.231; 5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239;5.J.157.154; 5.J.157.157; 5.J.157.166; 5.J.157.169; 5.J.157.172;5.J.157.175; 5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J.166.229;5.J.166.230; 5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238;5.J.166.239; 5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169;5.J.166.172; 5.J.166.175; 5.J.166.240; 5.J.166.244; 5.J.169.228;5.J.169.229; 5.J.169.230; 5.J.169.231; 5.J.169.236; 5.J.169.237;5.J.169.238; 5.J.169.239; 5.J.169.154; 5.J.169.157; 5.J.169.166;5.J.169.169; 5.J.169.172; 5.J.169.175; 5.J.169.240; 5.J.169.244;5.J.172.228; 5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236;5.J.172.237; 5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157;5.J.172.166; 5.J.172.169; 5.J.172.172; 5.J.172.175; 5.J.172.240;5.J.172.244; 5.J.175.228; 5.J.175.229; 5.J.175.230; 5.J.175.231;5.J.175.236; 5.J.175.237; 5.J.175.238; 5.J.175.239; 5.J.175.154;5.J.175.157; 5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175;5.J.175.240; 5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230;5.J.240.231; 5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239;5.J.240.154; 5.J.240.157; 5.J.240.166; 5.J.240.169; 5.J.240.172;5.J.240.175; 5.J.240.240; 5.J.240.244; 5.J.244.228; 5.J.244.229;5.J.244.230; 5.J.244.231; 5.J.244.236; 5.J.244.237; 5.J.244.238;5.J.244.239; 5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169;5.J.244.172; 5.J.244.175; 5.J.244.240; 5.J.244.244; Prodrugs of 5.L5.L.228.228; 5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236;5.L.228.237; 5.L.228.238; 5.L.228.239; 5.L.228.154; 5.L.228.157;5.L.228.166; 5.L.228.169; 5.L.228.172; 5.L.228.175; 5.L.228.240;5.L.228.244; 5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231;5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154;5.L.229.157; 5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175;5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230;5.L.230.231; 5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239;5.L.230.154; 5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172;5.L.230.175; 5.L.230.240; 5.L.230.244; 5.L.231.228; 5.L.231.229;5.L.231.230; 5.L.231.231; 5.L.231.236; 5.L.231.237; 5.L.231.238;5.L.231.239; 5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169;5.L.231.172; 5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L.236.228;5.L.236.229; 5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237;5.L.236.238; 5.L.236.239; 5.L.236.154; 5.L.236.157; 5.L.236.166;5.L.236.169; 5.L.236.172; 5.L.236.175; 5.L.236.240; 5.L.236.244;5.L.237.228; 5.L.237.229; 5.L.237.230; 5.L.237.231; 5.L.237.236;5.L.237.237; 5.L.237.238; 5.L.237.239; 5.L.237.154; 5.L.237.157;5.L.237.166; 5.L.237.169; 5.L.237.172; 5.L.237.175; 5.L.237.240;5.L.237.244; 5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231;5.L.238.236; 5.L.238.237; 5.L.238.238; 5.L.238.239; 5.L.238.154;5.L.238.157; 5.L.238.166; 5.L.238.169; 5.L.238.172; 5.L.238.175;5.L.238.240; 5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230;5.L.239.231; 5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239;5.L.239.154; 5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172;5.L.239.175; 5.L.239.240; 5.L.239.244; 5.L.154.228; 5.L.154.229;5.L.154.230; 5.L.154.231; 5.L.154.236; 5.L.154.237; 5.L.154.238;5.L.154.239; 5.L.154.154; 5.L.154.157; 5.L.154.166; 5.L.154.169;5.L.154.172; 5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228;5.L.157.229; 5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237;5.L.157.238; 5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166;5.L.157.169; 5.L.157.172; 5.L.157.175; 5.L.157.240; 5.L.157.244;5.L.166.228; 5.L.166.229; 5.L.166.230; 5.L.166.231; 5.L.166.236;5.L.166.237; 5.L.166.238; 5.L.166.239; 5.L.166.154; 5.L.166.157;5.L.166.166; 5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240;5.L.166.244; 5.L.169.228; 5.L.169.229; 5.L.169.230; 5.L.169.231;5.L.169.236; 5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154;5.L.169.157; 5.L.169.166; 5.L.169.169; 5.L.169.172; 5.L.169.175;5.L.169.240; 5.L.169.244; 5.L.172.228; 5.L.172.229; 5.L.172.230;5.L.172.231; 5.L.172.236; 5.L.172.237; 5.L.172.238; 5.L.172.239;5.L.172.154; 5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172;5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229;5.L.175.230; 5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238;5.L.175.239; 5.L.175.154; 5.L.175.157; 5.L.175.166; 5.L.175.169;5.L.175.172; 5.L.175.175; 5.L.175.240; 5.L.175.244; 5.L.240.228;5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237;5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166;5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244;5.L.244.228; 5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236;5.L.244.237; 5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157;5.L.244.166; 5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240;5.L.244.244; Prodrugs of 5.O 5.O.228.228; 5.O.228.229; 5.O.228.230;5.O.228.231; 5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239;5.O.228.154; 5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172;5.O.228.175; 5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229;5.O.229.230; 5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238;5.O.229.239; 5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169;5.O.229.172; 5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228;5.O.230.229; 5.O.230.230; 5.O.230.231; 5.O.230.236; 5.O.230.237;5.O.230.238; 5.O.230.239; 5.O.230.154; 5.O.230.157; 5.O.230.166;5.O.230.169; 5.O.230.172; 5.O.230.175; 5.O.230.240; 5.O.230.244;5.O.231.228; 5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236;5.O.231.237; 5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157;5.O.231.166; 5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240;5.O.231.244; 5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231;5.O.236.236; 5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154;5.O.236.157; 5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175;5.O.236.240; 5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230;5.O.237.231; 5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239;5.O.237.154; 5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172;5.O.237.175; 5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229;5.O.238.230; 5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238;5.O.238.239; 5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169;5.O.238.172; 5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228;5.O.239.229; 5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237;5.O.239.238; 5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166;5.O.239.169; 5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244;5.O.154.228; 5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236;5.O.154.237; 5.O.154.238; 5.O.154.239; 5.O.154.154; 5.O.154.157;5.O.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.154.240;5.O.154.244; 5.O.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231;5.O.157.236; 5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154;5.O.157.157; 5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175;5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230;5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239;5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172;5.O.166.175; 5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229;5.O.169.230; 5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238;5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169;5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228;5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237;5.O.172.238; 5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166;5.O.172.169; 5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244;5.O.175.228; 5.O.175.229; 5.O.175.230; 5.O.175.231; 5.O.175.236;5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157;5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240;5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231;5.O.240.236; 5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154;5.O.240.157; 5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175;5.O.240.240; 5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230;5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239;5.O.244.154; 5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172;5.O.244.175; 5.O.244.240; 5.O.244.244; Prodrugs of 5.P 5.P.228.228;5.P.228.229; 5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237;5.P.228.238; 5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166;5.P.228.169; 5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244;5.P.229.228; 5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236;5.P.229.237; 5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157;5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240;5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231;5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154;5.P.230.157; 5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175;5.P.230.240; 5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230;5.P.231.231; 5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239;5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172;5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229;5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238;5.P.236.239; 5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169;5.P.236.172; 5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228;5.P.237.229; 5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237;5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166;5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244;5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236;5.P.238.237; 5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157;5.P.238.166; 5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240;5.P.238.244; 5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231;5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154;5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175;5.P.239.240; 5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230;5.P.154.231; 5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239;5.P.154.154; 5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172;5.P.154.175; 5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P.157.229;5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238;5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169;5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228;5.P.166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237;5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166;5.P.166.169; 5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244;5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236;5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157;5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240;5.P.169.244; 5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231;5.P.172.236; 5.P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154;5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P.172.175;5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229; 5.P.175.230;5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239;5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172;5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229;5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P.240.238;5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166; 5.P.240.169;5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244; 5.P.244.228;5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237;5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166;5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;Prodrugs of 5.U 5.U.228.228; 5.U.228.229; 5.U.228.230; 5.U.228.231;5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239; 5.U.228.154;5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172; 5.U.228.175;5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.229.230;5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238; 5.U.229.239;5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172;5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228; 5.U.230.229;5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237; 5.U.230.238;5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166; 5.U.230.169;5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228;5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237;5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166;5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240; 5.U.231.244;5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231; 5.U.236.236;5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154; 5.U.236.157;5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175; 5.U.236.240;5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231;5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154;5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172; 5.U.237.175;5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229; 5.U.238.230;5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238; 5.U.238.239;5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172;5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229;5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238;5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166; 5.U.239.169;5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244; 5.U.154.228;5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236; 5.U.154.237;5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166;5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244;5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236;5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154; 5.U.157.157;5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175; 5.U.157.240;5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231;5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154;5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175;5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230;5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238; 5.U.169.239;5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172;5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229;5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238;5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169;5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228;5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237;5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166;5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240; 5.U.175.244;5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236;5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157;5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240;5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230; 5.U.244.231;5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239; 5.U.244.154;5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175;5.U.244.240; 5.U.244.244; Prodrugs of 5.W 5.W.228.228; 5.W.228.229;5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238;5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169;5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228;5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237;5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166;5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244;5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236;5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157;5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240;5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231;5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154;5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175;5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230;5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239;5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172;5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229;5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5.W.237.238;5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169;5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228;5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237;5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166;5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5.W.238.244;5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236;5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157;5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240;5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231;5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5.W.154.154;5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175;5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229; 5.W.157.230;5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239;5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172;5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229;5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237; 5.W.166.238;5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169;5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W.169.228;5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236; 5.W.169.237;5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166;5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244;5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236;5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157;5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175; 5.W.172.240;5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231;5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154;5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175;5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230;5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238; 5.W.240.239;5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169; 5.W.240.172;5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229;5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237; 5.W.244.238;5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169;5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244; Prodrugs of 5.Y5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236;5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157;5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175; 5.Y.228.240;5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230; 5.Y.229.231;5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239; 5.Y.229.154;5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175;5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230;5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239;5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169; 5.Y.230.172;5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228; 5.Y.231.229;5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237; 5.Y.231.238;5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169;5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228;5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237;5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157; 5.Y.236.166;5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240; 5.Y.236.244;5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231; 5.Y.237.236;5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157;5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240;5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231;5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239; 5.Y.238.154;5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172; 5.Y.238.175;5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229; 5.Y.239.230;5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239;5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172;5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229;5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237; 5.Y.154.238;5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166; 5.Y.154.169;5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244; 5.Y.157.228;5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237;5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166;5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244;5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231; 5.Y.166.236;5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154; 5.Y.166.157;5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175; 5.Y.166.240;5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231;5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154;5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175;5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229; 5.Y.172.230;5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238; 5.Y.172.239;5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172;5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229;5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238;5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166; 5.Y.175.169;5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244; 5.Y.240.228;5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236; 5.Y.240.237;5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166;5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244;5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236;5.Y.244.237; 5.Y.244.238; 5.Y.244.239; 5.Y.244.154; 5.Y.244.157;5.Y.244.166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175; 5.Y.244.240;5.Y.244.244; Prodrugs of 6.B 6.B.228.228; 6.B.228.229; 6.B.228.230;6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238; 6.B.228.239;6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169; 6.B.228.172;6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229;6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238;6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169;6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244; 6.B.230.228;6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236; 6.B.230.237;6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157; 6.B.230.166;6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244;6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236;6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157;6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175; 6.B.231.240;6.B.231.244; 6.B.236.228; 6.B.236.229; 6.B.236.230; 6.B.236.231;6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239; 6.B.236.154;6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175;6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230;6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239;6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169; 6.B.237.172;6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228; 6.B.238.229;6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237; 6.B.238.238;6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169;6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228;6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237;6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157; 6.B.239.166;6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240; 6.B.239.244;6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231; 6.B.154.236;6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157;6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240;6.B.154.244; 6.B.157.228; 6.B.157.229; 6.B.157.230; 6.B.157.231;6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239; 6.B.157.154;6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172; 6.B.157.175;6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229; 6.B.166.230;6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B.166.239;6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172;6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B.169.228; 6.B.169.229;6.B.169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237; 6.B.169.238;6.B.169.239; 6.B.169.154; 6.B.169.157; 6.B.169.166; 6.B.169.169;6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244; 6.B.172.228;6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236; 6.B.172.237;6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157; 6.B.172.166;6.B.172.169; 6.B.172.172; 6.B.172.175; 6.B.172.240; 6.B.172.244;6.B.175.228; 6.B.175.229; 6.B.175.230; 6.B.175.231; 6.B.175.236;6.B.175.237; 6.B.175.238; 6.B.175.239; 6.B.175.154; 6.B.175.157;6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175; 6.B.175.240;6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230; 6.B.240.231;6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239; 6.B.240.154;6.B.240.157; 6.B.240.166; 6.B.240.169; 6.B.240.172; 6.B.240.175;6.B.240.240; 6.B.240.244; 6.B.244.228; 6.B.244.229; 6.B.244.230;6.B.244.231; 6.B.244.236; 6.B.244.237; 6.B.244.238; 6.B.244.239;6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169; 6.B.244.172;6.B.244.175; 6.B.244.240; 6.B.244.244; Prodrugs of 6.D 6.D.228.228;6.D.228.229; 6.D.228.230; 6.D.228.231; 6.D.228.236; 6.D.228.237;6.D.228.238; 6.D.228.239; 6.D.228.154; 6.D.228.157; 6.D.228.166;6.D.228.169; 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6.D.244.172; 6.D.244.175; 6.D.244.240; 6.D.244.244;Prodrugs of 6.E 6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231;6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239; 6.E.228.154;6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172; 6.E.228.175;6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229; 6.E.229.230;6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239;6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169; 6.E.229.172;6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229;6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237; 6.E.230.238;6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166; 6.E.230.169;6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244; 6.E.231.228;6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237;6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166;6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244;6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231; 6.E.236.236;6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154; 6.E.236.157;6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175; 6.E.236.240;6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230; 6.E.237.231;6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239; 6.E.237.154;6.E.237.157; 6.E.237.166; 6.E.237.169; 6.E.237.172; 6.E.237.175;6.E.237.240; 6.E.237.244; 6.E.238.228; 6.E.238.229; 6.E.238.230;6.E.238.231; 6.E.238.236; 6.E.238.237; 6.E.238.238; 6.E.238.239;6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169; 6.E.238.172;6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228; 6.E.239.229;6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237; 6.E.239.238;6.E.239.239; 6.E.239.154; 6.E.239.157; 6.E.239.166; 6.E.239.169;6.E.239.172; 6.E.239.175; 6.E.239.240; 6.E.239.244; 6.E.154.228;6.E.154.229; 6.E.154.230; 6.E.154.231; 6.E.154.236; 6.E.154.237;6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157; 6.E.154.166;6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240; 6.E.154.244;6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231; 6.E.157.236;6.E.157.237; 6.E.157.238; 6.E.157.239; 6.E.157.154; 6.E.157.157;6.E.157.166; 6.E.157.169; 6.E.157.172; 6.E.157.175; 6.E.157.240;6.E.157.244; 6.E.166.228; 6.E.166.229; 6.E.166.230; 6.E.166.231;6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239; 6.E.166.154;6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172; 6.E.166.175;6.E.166.240; 6.E.166.244; 6.E.169.228; 6.E.169.229; 6.E.169.230;6.E.169.231; 6.E.169.236; 6.E.169.237; 6.E.169.238; 6.E.169.239;6.E.169.154; 6.E.169.157; 6.E.169.166; 6.E.169.169; 6.E.169.172;6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228; 6.E.172.229;6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237; 6.E.172.238;6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166; 6.E.172.169;6.E.172.172; 6.E.172.175; 6.E.172.240; 6.E.172.244; 6.E.175.228;6.E.175.229; 6.E.175.230; 6.E.175.231; 6.E.175.236; 6.E.175.237;6.E.175.238; 6.E.175.239; 6.E.175.154; 6.E.175.157; 6.E.175.166;6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240; 6.E.175.244;6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231; 6.E.240.236;6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154; 6.E.240.157;6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240;6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230; 6.E.244.231;6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239; 6.E.244.154;6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172; 6.E.244.175;6.E.244.240; 6.E.244.244; Prodrugs of 6.G 6.G.228.228; 6.G.228.229;6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237; 6.G.228.238;6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166; 6.G.228.169;6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244; 6.G.229.228;6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237;6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157; 6.G.229.166;6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240; 6.G.229.244;6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231; 6.G.230.236;6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157;6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240;6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231;6.G.231.236; 6.G.231.237; 6.G.231.238; 6.G.231.239; 6.G.231.154;6.G.231.157; 6.G.231.166; 6.G.231.169; 6.G.231.172; 6.G.231.175;6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G.236.229; 6.G.236.230;6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238; 6.G.236.239;6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169; 6.G.236.172;6.G.236.175; 6.G.236.240; 6.G.236.244; 6.G.237.228; 6.G.237.229;6.G.237.230; 6.G.237.231; 6.G.237.236; 6.G.237.237; 6.G.237.238;6.G.237.239; 6.G.237.154; 6.G.237.157; 6.G.237.166; 6.G.237.169;6.G.237.172; 6.G.237.175; 6.G.237.240; 6.G.237.244; 6.G.238.228;6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236; 6.G.238.237;6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157; 6.G.238.166;6.G.238.169; 6.G.238.172; 6.G.238.175; 6.G.238.240; 6.G.238.244;6.G.239.228; 6.G.239.229; 6.G.239.230; 6.G.239.231; 6.G.239.236;6.G.239.237; 6.G.239.238; 6.G.239.239; 6.G.239.154; 6.G.239.157;6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175; 6.G.239.240;6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230; 6.G.154.231;6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154;6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175;6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G.157.229; 6.G.157.230;6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238; 6.G.157.239;6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169; 6.G.157.172;6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G.166.229;6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238;6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169;6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244; 6.G.169.228;6.G.169.229; 6.G.169.230; 6.G.169.231; 6.G.169.236; 6.G.169.237;6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157; 6.G.169.166;6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244;6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236;6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157;6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175; 6.G.172.240;6.G.172.244; 6.G.175.228; 6.G.175.229; 6.G.175.230; 6.G.175.231;6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239; 6.G.175.154;6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175;6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230;6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239;6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169; 6.G.240.172;6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228; 6.G.244.229;6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237; 6.G.244.238;6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169;6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244; Prodrugs of 6.I6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231; 6.I.228.236;6.I.228.237; 6.I.228.238; 6.I.228.239; 6.I.228.154; 6.I.228.157;6.I.228.166; 6.I.228.169; 6.I.228.172; 6.I.228.175; 6.I.228.240;6.I.228.244; 6.I.229.228; 6.I.229.229; 6.I.229.230; 6.I.229.231;6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239; 6.I.229.154;6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172; 6.I.229.175;6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229; 6.I.230.230;6.I.230.231; 6.I.230.236; 6.I.230.237; 6.I.230.238; 6.I.230.239;6.I.230.154; 6.I.230.157; 6.I.230.166; 6.I.230.169; 6.I.230.172;6.I.230.175; 6.I.230.240; 6.I.230.244; 6.I.231.228; 6.I.231.229;6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237; 6.I.231.238;6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166; 6.I.231.169;6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244; 6.I.236.228;6.I.236.229; 6.I.236.230; 6.I.236.231; 6.I.236.236; 6.I.236.237;6.I.236.238; 6.I.236.239; 6.I.236.154; 6.I.236.157; 6.I.236.166;6.I.236.169; 6.I.236.172; 6.I.236.175; 6.I.236.240; 6.I.236.244;6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231; 6.I.237.236;6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154; 6.I.237.157;6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175; 6.I.237.240;6.I.237.244; 6.I.238.228; 6.I.238.229; 6.I.238.230; 6.I.238.231;6.I.238.236; 6.I.238.237; 6.I.238.238; 6.I.238.239; 6.I.238.154;6.I.238.157; 6.I.238.166; 6.I.238.169; 6.I.238.172; 6.I.238.175;6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229; 6.I.239.230;6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238; 6.I.239.239;6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169; 6.I.239.172;6.I.239.175; 6.I.239.240; 6.I.239.244; 6.I.154.228; 6.I.154.229;6.I.154.230; 6.I.154.231; 6.I.154.236; 6.I.154.237; 6.I.154.238;6.I.154.239; 6.I.154.154; 6.I.154.157; 6.I.154.166; 6.I.154.169;6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244; 6.I.157.228;6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236; 6.I.157.237;6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157; 6.I.157.166;6.I.157.169; 6.I.157.172; 6.I.157.175; 6.I.157.240; 6.I.157.244;6.I.166.228; 6.I.166.229; 6.I.166.230; 6.I.166.231; 6.I.166.236;6.I.166.237; 6.I.166.238; 6.I.166.239; 6.I.166.154; 6.I.166.157;6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175; 6.I.166.240;6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230; 6.I.169.231;6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239; 6.I.169.154;6.I.169.157; 6.I.169.166; 6.I.169.169; 6.I.169.172; 6.I.169.175;6.I.169.240; 6.I.169.244; 6.I.172.228; 6.I.172.229; 6.I.172.230;6.I.172.231; 6.I.172.236; 6.I.172.237; 6.I.172.238; 6.I.172.239;6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169; 6.I.172.172;6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228; 6.I.175.229;6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237; 6.I.175.238;6.I.175.239; 6.I.175.154; 6.I.175.157; 6.I.175.166; 6.I.175.169;6.I.175.172; 6.I.175.175; 6.I.175.240; 6.I.175.244; 6.I.240.228;6.I.240.229; 6.I.240.230; 6.I.240.231; 6.I.240.236; 6.I.240.237;6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157; 6.I.240.166;6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240; 6.I.240.244;6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231; 6.I.244.236;6.I.244.237; 6.I.244.238; 6.I.244.239; 6.I.244.154; 6.I.244.157;6.I.244.166; 6.I.244.169; 6.I.244.172; 6.I.244.175; 6.I.244.240;6.I.244.244; Prodrugs of 6.J 6.J.228.228; 6.J.228.229; 6.J.228.230;6.J.228.231; 6.J.228.236; 6.J.228.237; 6.J.228.238; 6.J.228.239;6.J.228.154; 6.J.228.157; 6.J.228.166; 6.J.228.169; 6.J.228.172;6.J.228.175; 6.J.228.240; 6.J.228.244; 6.J.229.228; 6.J.229.229;6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237; 6.J.229.238;6.J.229.239; 6.J.229.154; 6.J.229.157; 6.J.229.166; 6.J.229.169;6.J.229.172; 6.J.229.175; 6.J.229.240; 6.J.229.244; 6.J.230.228;6.J.230.229; 6.J.230.230; 6.J.230.231; 6.J.230.236; 6.J.230.237;6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J.230.157; 6.J.230.166;6.J.230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240; 6.J.230.244;6.J.231.228; 6.J.231.229; 6.J.231.230; 6.J.231.231; 6.J.231.236;6.J.231.237; 6.J.231.238; 6.J.231.239; 6.J.231.154; 6.J.231.157;6.J.231.166; 6.J.231.169; 6.J.231.172; 6.J.231.175; 6.J.231.240;6.J.231.244; 6.J.236.228; 6.J.236.229; 6.J.236.230; 6.J.236.231;6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239; 6.J.236.154;6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172; 6.J.236.175;6.J.236.240; 6.J.236.244; 6.J.237.228; 6.J.237.229; 6.J.237.230;6.J.237.231; 6.J.237.236; 6.J.237.237; 6.J.237.238; 6.J.237.239;6.J.237.154; 6.J.237.157; 6.J.237.166; 6.J.237.169; 6.J.237.172;6.J.237.175; 6.J.237.240; 6.J.237.244; 6.J.238.228; 6.J.238.229;6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237; 6.J.238.238;6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J.238.166; 6.J.238.169;6.J.238.172; 6.J.238.175; 6.J.238.240; 6.J.238.244; 6.J.239.228;6.J.239.229; 6.J.239.230; 6.J.239.231; 6.J.239.236; 6.J.239.237;6.J.239.238; 6.J.239.239; 6.J.239.154; 6.J.239.157; 6.J.239.166;6.J.239.169; 6.J.239.172; 6.J.239.175; 6.J.239.240; 6.J.239.244;6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231; 6.J.154.236;6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154; 6.J.154.157;6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175; 6.J.154.240;6.J.154.244; 6.J.157.228; 6.J.157.229; 6.J.157.230; 6.J.157.231;6.J.157.236; 6.J.157.237; 6.J.157.238; 6.J.157.239; 6.J.157.154;6.J.157.157; 6.J.157.166; 6.J.157.169; 6.J.157.172; 6.J.157.175;6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J.166.229; 6.J.166.230;6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238; 6.J.166.239;6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169; 6.J.166.172;6.J.166.175; 6.J.166.240; 6.J.166.244; 6.J.169.228; 6.J.169.229;6.J.169.230; 6.J.169.231; 6.J.169.236; 6.J.169.237; 6.J.169.238;6.J.169.239; 6.J.169.154; 6.J.169.157; 6.J.169.166; 6.J.169.169;6.J.169.172; 6.J.169.175; 6.J.169.240; 6.J.169.244; 6.J.172.228;6.J.172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236; 6.J.172.237;6.J.172.238; 6.J.172.239; 6.J.172.154; 6.J.172.157; 6.J.172.166;6.J.172.169; 6.J.172.172; 6.J.172.175; 6.J.172.240; 6.J.172.244;6.J.175.228; 6.J.175.229; 6.J.175.230; 6.J.175.231; 6.J.175.236;6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154; 6.J.175.157;6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175; 6.J.175.240;6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230; 6.J.240.231;6.J.240.236; 6.J.240.237; 6.J.240.238; 6.J.240.239; 6.J.240.154;6.J.240.157; 6.J.240.166; 6.J.240.169; 6.J.240.172; 6.J.240.175;6.J.240.240; 6.J.240.244; 6.J.244.228; 6.J.244.229; 6.J.244.230;6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238; 6.J.244.239;6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169; 6.J.244.172;6.J.244.175; 6.J.244.240; 6.J.244.244; Prodrugs of 6.L 6.L.228.228;6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236; 6.L.228.237;6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157; 6.L.228.166;6.L.228.169; 6.L.228.172; 6.L.228.175; 6.L.228.240; 6.L.228.244;6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231; 6.L.229.236;6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154; 6.L.229.157;6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175; 6.L.229.240;6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230; 6.L.230.231;6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239; 6.L.230.154;6.L.230.157; 6.L.230.166; 6.L.230.169; 6.L.230.172; 6.L.230.175;6.L.230.240; 6.L.230.244; 6.L.231.228; 6.L.231.229; 6.L.231.230;6.L.231.231; 6.L.231.236; 6.L.231.237; 6.L.231.238; 6.L.231.239;6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169; 6.L.231.172;6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228; 6.L.236.229;6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237; 6.L.236.238;6.L.236.239; 6.L.236.154; 6.L.236.157; 6.L.236.166; 6.L.236.169;6.L.236.172; 6.L.236.175; 6.L.236.240; 6.L.236.244; 6.L.237.228;6.L.237.229; 6.L.237.230; 6.L.237.231; 6.L.237.236; 6.L.237.237;6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157; 6.L.237.166;6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240; 6.L.237.244;6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231; 6.L.238.236;6.L.238.237; 6.L.238.238; 6.L.238.239; 6.L.238.154; 6.L.238.157;6.L.238.166; 6.L.238.169; 6.L.238.172; 6.L.238.175; 6.L.238.240;6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230; 6.L.239.231;6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239; 6.L.239.154;6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175;6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229; 6.L.154.230;6.L.154.231; 6.L.154.236; 6.L.154.237; 6.L.154.238; 6.L.154.239;6.L.154.154; 6.L.154.157; 6.L.154.166; 6.L.154.169; 6.L.154.172;6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L.157.228; 6.L.157.229;6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237; 6.L.157.238;6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166; 6.L.157.169;6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228;6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237;6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157; 6.L.166.166;6.L.166.169; 6.L.166.172; 6.L.166.175; 6.L.166.240; 6.L.166.244;6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231; 6.L.169.236;6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157;6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240;6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231;6.L.172.236; 6.L.172.237; 6.L.172.238; 6.L.172.239; 6.L.172.154;6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172; 6.L.172.175;6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229; 6.L.175.230;6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239;6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172;6.L.175.175; 6.L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229;6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L.240.238;6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166; 6.L.240.169;6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244; 6.L.244.228;6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237;6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166;6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;Prodrugs of 6.O 6.O.228.228; 6.O.228.229; 6.O.228.230; 6.O.228.231;6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239; 6.O.228.154;6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172; 6.O.228.175;6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229; 6.O.229.230;6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238; 6.O.229.239;6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169; 6.O.229.172;6.O.229.175; 6.O.229.240; 6.O.229.244; 6.O.230.228; 6.O.230.229;6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237; 6.O.230.238;6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166; 6.O.230.169;6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244; 6.O.231.228;6.O.231.229; 6.O.231.230; 6.O.231.231; 6.O.231.236; 6.O.231.237;6.O.231.238; 6.O.231.239; 6.O.231.154; 6.O.231.157; 6.O.231.166;6.O.231.169; 6.O.231.172; 6.O.231.175; 6.O.231.240; 6.O.231.244;6.O.236.228; 6.O.236.229; 6.O.236.230; 6.O.236.231; 6.O.236.236;6.O.236.237; 6.O.236.238; 6.O.236.239; 6.O.236.154; 6.O.236.157;6.O.236.166; 6.O.236.169; 6.O.236.172; 6.O.236.175; 6.O.236.240;6.O.236.244; 6.O.237.228; 6.O.237.229; 6.O.237.230; 6.O.237.231;6.O.237.236; 6.O.237.237; 6.O.237.238; 6.O.237.239; 6.O.237.154;6.O.237.157; 6.O.237.166; 6.O.237.169; 6.O.237.172; 6.O.237.175;6.O.237.240; 6.O.237.244; 6.O.238.228; 6.O.238.229; 6.O.238.230;6.O.238.231; 6.O.238.236; 6.O.238.237; 6.O.238.238; 6.O.238.239;6.O.238.154; 6.O.238.157; 6.O.238.166; 6.O.238.169; 6.O.238.172;6.O.238.175; 6.O.238.240; 6.O.238.244; 6.O.239.228; 6.O.239.229;6.O.239.230; 6.O.239.231; 6.O.239.236; 6.O.239.237; 6.O.239.238;6.O.239.239; 6.O.239.154; 6.O.239.157; 6.O.239.166; 6.O.239.169;6.O.239.172; 6.O.239.175; 6.O.239.240; 6.O.239.244; 6.O.154.228;6.O.154.229; 6.O.154.230; 6.O.154.231; 6.O.154.236; 6.O.154.237;6.O.154.238; 6.O.154.239; 6.O.154.154; 6.O.154.157; 6.O.154.166;6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240; 6.O.154.244;6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231; 6.O.157.236;6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154; 6.O.157.157;6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175; 6.O.157.240;6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231;6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154;6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175;6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230;6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238; 6.O.169.239;6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172;6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229;6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237; 6.O.172.238;6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169;6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228;6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237;6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166;6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240; 6.O.175.244;6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236;6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157;6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240;6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230; 6.O.244.231;6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239; 6.O.244.154;6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172; 6.O.244.175;6.O.244.240; 6.O.244.244; Prodrugs of 6.P 6.P.228.228; 6.P.228.229;6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237; 6.P.228.238;6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166; 6.P.228.169;6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244; 6.P.229.228;6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237;6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157; 6.P.229.166;6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240; 6.P.229.244;6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231; 6.P.230.236;6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154; 6.P.230.157;6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175; 6.P.230.240;6.P.230.244; 6.P.231.228; 6.P.231.229; 6.P.231.230; 6.P.231.231;6.P.231.236; 6.P.231.237; 6.P.231.238; 6.P.231.239; 6.P.231.154;6.P.231.157; 6.P.231.166; 6.P.231.169; 6.P.231.172; 6.P.231.175;6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229; 6.P.236.230;6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238; 6.P.236.239;6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169; 6.P.236.172;6.P.236.175; 6.P.236.240; 6.P.236.244; 6.P.237.228; 6.P.237.229;6.P.237.230; 6.P.237.231; 6.P.237.236; 6.P.237.237; 6.P.237.238;6.P.237.239; 6.P.237.154; 6.P.237.157; 6.P.237.166; 6.P.237.169;6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244; 6.P.238.228;6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236; 6.P.238.237;6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157; 6.P.238.166;6.P.238.169; 6.P.238.172; 6.P.238.175; 6.P.238.240; 6.P.238.244;6.P.239.228; 6.P.239.229; 6.P.239.230; 6.P.239.231; 6.P.239.236;6.P.239.237; 6.P.239.238; 6.P.239.239; 6.P.239.154; 6.P.239.157;6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175; 6.P.239.240;6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230; 6.P.154.231;6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239; 6.P.154.154;6.P.154.157; 6.P.154.166; 6.P.154.169; 6.P.154.172; 6.P.154.175;6.P.154.240; 6.P.154.244; 6.P.157.228; 6.P.157.229; 6.P.157.230;6.P.157.231; 6.P.157.236; 6.P.157.237; 6.P.157.238; 6.P.157.239;6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169; 6.P.157.172;6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228; 6.P.166.229;6.P.166.230; 6.P.166.231; 6.P.166.236; 6.P.166.237; 6.P.166.238;6.P.166.239; 6.P.166.154; 6.P.166.157; 6.P.166.166; 6.P.166.169;6.P.166.172; 6.P.166.175; 6.P.166.240; 6.P.166.244; 6.P.169.228;6.P.169.229; 6.P.169.230; 6.P.169.231; 6.P.169.236; 6.P.169.237;6.P.169.238; 6.P.169.239; 6.P.169.154; 6.P.169.157; 6.P.169.166;6.P.169.169; 6.P.169.172; 6.P.169.175; 6.P.169.240; 6.P.169.244;6.P.172.228; 6.P.172.229; 6.P.172.230; 6.P.172.231; 6.P.172.236;6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154; 6.P.172.157;6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175; 6.P.172.240;6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230; 6.P.175.231;6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154;6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175;6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230;6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238; 6.P.240.239;6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169; 6.P.240.172;6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228; 6.P.244.229;6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238;6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169;6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244; Prodrugs of 6.U6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236;6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157;6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175; 6.U.228.240;6.U.228.244; 6.U.229.228; 6.U.229.229; 6.U.229.230; 6.U.229.231;6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239; 6.U.229.154;6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172; 6.U.229.175;6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229; 6.U.230.230;6.U.230.231; 6.U.230.236; 6.U.230.237; 6.U.230.238; 6.U.230.239;6.U.230.154; 6.U.230.157; 6.U.230.166; 6.U.230.169; 6.U.230.172;6.U.230.175; 6.U.230.240; 6.U.230.244; 6.U.231.228; 6.U.231.229;6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237; 6.U.231.238;6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166; 6.U.231.169;6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244; 6.U.236.228;6.U.236.229; 6.U.236.230; 6.U.236.231; 6.U.236.236; 6.U.236.237;6.U.236.238; 6.U.236.239; 6.U.236.154; 6.U.236.157; 6.U.236.166;6.U.236.169; 6.U.236.172; 6.U.236.175; 6.U.236.240; 6.U.236.244;6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231; 6.U.237.236;6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154; 6.U.237.157;6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175; 6.U.237.240;6.U.237.244; 6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231;6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239; 6.U.238.154;6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172; 6.U.238.175;6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229; 6.U.239.230;6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239;6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172;6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229;6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237; 6.U.154.238;6.U.154.239; 6.U.154.154; 6.U.154.157; 6.U.154.166; 6.U.154.169;6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244; 6.U.157.228;6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237;6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166;6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244;6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231; 6.U.166.236;6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154; 6.U.166.157;6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175; 6.U.166.240;6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231;6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154;6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175;6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229; 6.U.172.230;6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238; 6.U.172.239;6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169; 6.U.172.172;6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229;6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238;6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169;6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244; 6.U.240.228;6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236; 6.U.240.237;6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157; 6.U.240.166;6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244;6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236;6.U.244.237; 6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157;6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175; 6.U.244.240;6.U.244.244; Prodrugs of 6.W 6.W.228.228; 6.W.228.229; 6.W.228.230;6.W.228.231; 6.W.228.236; 6.W.228.237; 6.W.228.238; 6.W.228.239;6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169; 6.W.228.172;6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228; 6.W.229.229;6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238;6.W.229.239; 6.W.229.154; 6.W.229.157; 6.W.229.166; 6.W.229.169;6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244; 6.W.230.228;6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236; 6.W.230.237;6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157; 6.W.230.166;6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244;6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236;6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157;6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175; 6.W.231.240;6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230; 6.W.236.231;6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239; 6.W.236.154;6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175;6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229; 6.W.237.230;6.W.237.231; 6.W.237.236; 6.W.237.237; 6.W.237.238; 6.W.237.239;6.W.237.154; 6.W.237.157; 6.W.237.166; 6.W.237.169; 6.W.237.172;6.W.237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228; 6.W.238.229;6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237; 6.W.238.238;6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169;6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228;6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237;6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157; 6.W.239.166;6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240; 6.W.239.244;6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231; 6.W.154.236;6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157;6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240;6.W.154.244; 6.W.157.228; 6.W.157.229; 6.W.157.230; 6.W.157.231;6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239; 6.W.157.154;6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172; 6.W.157.175;6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229; 6.W.166.230;6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239;6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172;6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W.169.228; 6.W.169.229;6.W.169.230; 6.W.169.231; 6.W.169.236; 6.W.169.237; 6.W.169.238;6.W.169.239; 6.W.169.154; 6.W.169.157; 6.W.169.166; 6.W.169.169;6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244; 6.W.172.228;6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237;6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166;6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244;6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231; 6.W.175.236;6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154; 6.W.175.157;6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175; 6.W.175.240;6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231;6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154;6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175;6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229; 6.W.244.230;6.W.244.231; 6.W.244.236; 6.W.244.237; 6.W.244.238; 6.W.244.239;6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169; 6.W.244.172;6.W.244.175; 6.W.244.240; 6.W.244.244; Prodrugs of 6.Y 6.Y.228.228;6.Y.228.229; 6.Y.228.230; 6.Y.228.231; 6.Y.228.236; 6.Y.228.237;6.Y.228.238; 6.Y.228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166;6.Y.228.169; 6.Y.228.172; 6.Y.228.175; 6.Y.228.240; 6.Y.228.244;6.Y.229.228; 6.Y.229.229; 6.Y.229.230; 6.Y.229.231; 6.Y.229.236;6.Y.229.237; 6.Y.229.238; 6.Y.229.239; 6.Y.229.154; 6.Y.229.157;6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175; 6.Y.229.240;6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231;6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154;6.Y.230.157; 6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175;6.Y.230.240; 6.Y.230.244; 6.Y.231.228; 6.Y.231.229; 6.Y.231.230;6.Y.231.231; 6.Y.231.236; 6.Y.231.237; 6.Y.231.238; 6.Y.231.239;6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169; 6.Y.231.172;6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229;6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238;6.Y.236.239; 6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169;6.Y.236.172; 6.Y.236.175; 6.Y.236.240; 6.Y.236.244; 6.Y.237.228;6.Y.237.229; 6.Y.237.230; 6.Y.237.231; 6.Y.237.236; 6.Y.237.237;6.Y.237.238; 6.Y.237.239; 6.Y.237.154; 6.Y.237.157; 6.Y.237.166;6.Y.237.169; 6.Y.237.172; 6.Y.237.175; 6.Y.237.240; 6.Y.237.244;6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236;6.Y.238.237; 6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157;6.Y.238.166; 6.Y.238.169; 6.Y.238.172; 6.Y.238.175; 6.Y.238.240;6.Y.238.244; 6.Y.239.228; 6.Y.239.229; 6.Y.239.230; 6.Y.239.231;6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239; 6.Y.239.154;6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175;6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230;6.Y.154.231; 6.Y.154.236; 6.Y.154.237; 6.Y.154.238; 6.Y.154.239;6.Y.154.154; 6.Y.154.157; 6.Y.154.166; 6.Y.154.169; 6.Y.154.172;6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228; 6.Y.157.229;6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y.157.238;6.Y.157.239; 6.Y.157.154; 6.Y.157.157; 6.Y.157.166; 6.Y.157.169;6.Y.157.172; 6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228;6.Y.166.229; 6.Y.166.230; 6.Y.166.231; 6.Y.166.236; 6.Y.166.237;6.Y.166.238; 6.Y.166.239; 6.Y.166.154; 6.Y.166.157; 6.Y.166.166;6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240; 6.Y.166.244;6.Y.169.228; 6.Y.169.229; 6.Y.169.230; 6.Y.169.231; 6.Y.169.236;6.Y.169.237; 6.Y.169.238; 6.Y.169.239; 6.Y.169.154; 6.Y.169.157;6.Y.169.166; 6.Y.169.169; 6.Y.169.172; 6.Y.169.175; 6.Y.169.240;6.Y.169.244; 6.Y.172.228; 6.Y.172.229; 6.Y.172.230; 6.Y.172.231;6.Y.172.236; 6.Y.172.237; 6.Y.172.238; 6.Y.172.239; 6.Y.172.154;6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y.172.172; 6.Y.172.175;6.Y.172.240; 6.Y.172.244; 6.Y.175.228; 6.Y.175.229; 6.Y.175.230;6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239;6.Y.175.154; 6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172;6.Y.175.175; 6.Y.175.240; 6.Y.175.244; 6.Y.240.228; 6.Y.240.229;6.Y.240.230; 6.Y.240.231; 6.Y.240.236; 6.Y.240.237; 6.Y.240.238;6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166; 6.Y.240.169;6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228;6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237;6.Y.244.238; 6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166;6.Y.244.169; 6.Y.244.172; 6.Y.244.175; 6.Y.244.240; 6.Y.244.244;Prodrugs of 7.AH 7.AH.4.157; 7.AH.4.158; 7.AH.4.196; 7.AH.4.223;7.AH.4.240; 7.AH.4.244; 7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158;7.AH.5.196; 7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247;7.AH.7.157; 7.AH.7.158; 7.AH.7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244;7.AH.7.243; 7.AH.7.247; 7.AH.15.157; 7.AH.15.158; 7.AH.15.196;7.AH.15.223; 7.AH.15.240; 7.AH.15.244; 7.AH.15.243; 7.AH.15.247;7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223; 7.AH.16.240;7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157; 7.AH.18.158;7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244; 7.AH.18.243;7.AH.18.247; 7.AH.26.157; 7.AH.26.158; 7.AH.26.196; 7.AH.26.223;7.AH.26.240; 7.AH.26.244; 7.AH.26.243; 7.AH.26.247; 7.AH.27.157;7.AH.27.158; 7.AH.27.196; 7.AH.27.223; 7.AH.27.240; 7.AH.27.244;7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158; 7.AH.29.196;7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247;7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223; 7.AH.54.240;7.AH.54.244; 7.AH.54.243; 7.AH.54.247; 7.AH.55.157; 7.AH.55.158;7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244; 7.AH.55.243;7.AH.55.247; 7.AH.56.157; 7.AH.56.158; 7.AH.56.196; 7.AH.56.223;7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247; 7.AH.157.157;7.AH.157.158; 7.AH.157.196; 7.AH.157.223; 7.AH.157.240; 7.AH.157.244;7.AH.157.243; 7.AH.157.247; 7.AH.196.157; 7.AH.196.158; 7.AH.196.196;7.AH.196.223; 7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247;7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240;7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH.240.157; 7.AH.240.158;7.AH.240.196; 7.AH.240.223; 7.AH.240.240; 7.AH.240.244; 7.AH.240.243;7.AH.240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223;7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH.247.157;7.AH.247.158; 7.AH.247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244;7.AH.247.243; 7.AH.247.247; Prodrugs of 7.AJ 7.AJ.4.157; 7.AJ.4.158;7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247;7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244;7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223;7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157;7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ.15.240; 7.AJ.15.244;7.AJ.15.243; 7.AJ.15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196;7.AJ.16.223; 7.AJ.16.240; 7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247;7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196; 7.AJ.18.223; 7.AJ.18.240;7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157; 7.AJ.26.158;7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243;7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223;7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157;7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244;7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157; 7.AJ.54.158; 7.AJ.54.196;7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243; 7.AJ.54.247;7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240;7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158;7.AJ.56.196; 7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243;7.AJ.56.247; 7.AJ.157.157; 7.AJ.157.158; 7.AJ.157.196; 7.AJ.157.223;7.AJ.157.240; 7.AJ.157.244; 7.AJ.157.243; 7.AJ.157.247; 7.AJ.196.157;7.AJ.196.158; 7.AJ.196.196; 7.AJ.196.223; 7.AJ.196.240; 7.AJ.196.244;7.AJ.196.243; 7.AJ.196.247; 7.AJ.223.157; 7.AJ.223.158; 7.AJ.223.196;7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243; 7.AJ.223.247;7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196; 7.AJ.240.223; 7.AJ.240.240;7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158;7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240; 7.AJ.244.244; 7.AJ.244.243;7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158; 7.AJ.247.196; 7.AJ.247.223;7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243; 7.AJ.247.247; Prodrugs of 7.AN7.AN.4.157; 7.AN.4.158; 7.AN.4.196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244;7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223;7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158;7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247;7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223; 7.AN.15.240;7.AN.15.244; 7.AN.15.243; 7.AN.15.247; 7.AN.16.157; 7.AN.16.158;7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244; 7.AN.16.243;7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196; 7.AN.18.223;7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247; 7.AN.26.157;7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244;7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196;7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247;7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223; 7.AN.29.240;7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157; 7.AN.54.158;7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244; 7.AN.54.243;7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223;7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157;7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244;7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158; 7.AN.157.196;7.AN.157.223; 7.AN.157.240; 7.AN.157.244; 7.AN.157.243; 7.AN.157.247;7.AN.196.157; 7.AN.196.158; 7.AN.196.196; 7.AN.196.223; 7.AN.196.240;7.AN.196.244; 7.AN.196.243; 7.AN.196.247; 7.AN.223.157; 7.AN.223.158;7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244; 7.AN.223.243;7.AN.223.247; 7.AN.240.157; 7.AN.240.158; 7.AN.240.196; 7.AN.240.223;7.AN.240.240; 7.AN.240.244; 7.AN.240.243; 7.AN.240.247; 7.AN.244.157;7.AN.244.158; 7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244;7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158; 7.AN.247.196;7.AN.247.223; 7.AN.247.240; 7.AN.247.244; 7.AN.247.243; 7.AN.247.247;Prodrugs of 7.AP 7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223;7.AP.4.240; 7.AP.4.244; 7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158;7.AP.5.196; 7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247;7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244;7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP.15.158; 7.AP.15.196;7.AP.15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243; 7.AP.15.247;7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223; 7.AP.16.240;7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157; 7.AP.18.158;7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244; 7.AP.18.243;7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223;7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247; 7.AP.27.157;7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240; 7.AP.27.244;7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158; 7.AP.29.196;7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247;7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240;7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158;7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244; 7.AP.55.243;7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196; 7.AP.56.223;7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247; 7.AP.157.157;7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240; 7.AP.157.244;7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158; 7.AP.196.196;7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247;7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223; 7.AP.223.240;7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157; 7.AP.240.158;7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244; 7.AP.240.243;7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223;7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157;7.AP.247.158; 7.AP.247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244;7.AP.247.243; 7.AP.247.247; Prodrugs of 7.AZ 7.AZ.4.157; 7.AZ.4.158;7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240; 7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247;7.AZ.5.157; 7.AZ.5.158; 7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244;7.AZ.5.243; 7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223;7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ.15.157;7.AZ.15.158; 7.AZ.15.196; 7.AZ.15.223; 7.AZ.15.240; 7.AZ.15.244;7.AZ.15.243; 7.AZ.15.247; 7.AZ.16.157; 7.AZ.16.158; 7.AZ.16.196;7.AZ.16.223; 7.AZ.16.240; 7.AZ.16.244; 7.AZ.16.243; 7.AZ.16.247;7.AZ.18.157; 7.AZ.18.158; 7.AZ.18.196; 7.AZ.18.223; 7.AZ.18.240;7.AZ.18.244; 7.AZ.18.243; 7.AZ.18.247; 7.AZ.26.157; 7.AZ.26.158;7.AZ.26.196; 7.AZ.26.223; 7.AZ.26.240; 7.AZ.26.244; 7.AZ.26.243;7.AZ.26.247; 7.AZ.27.157; 7.AZ.27.158; 7.AZ.27.196; 7.AZ.27.223;7.AZ.27.240; 7.AZ.27.244; 7.AZ.27.243; 7.AZ.27.247; 7.AZ.29.157;7.AZ.29.158; 7.AZ.29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244;7.AZ.29.243; 7.AZ.29.247; 7.AZ.54.157; 7.AZ.54.158; 7.AZ.54.196;7.AZ.54.223; 7.AZ.54.240; 7.AZ.54.244; 7.AZ.54.243; 7.AZ.54.247;7.AZ.55.157; 7.AZ.55.158; 7.AZ.55.196; 7.AZ.55.223; 7.AZ.55.240;7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ.56.157; 7.AZ.56.158;7.AZ.56.196; 7.AZ.56.223; 7.AZ.56.240; 7.AZ.56.244; 7.AZ.56.243;7.AZ.56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196; 7.AZ.157.223;7.AZ.157.240; 7.AZ.157.244; 7.AZ.157.243; 7.AZ.157.247; 7.AZ.196.157;7.AZ.196.158; 7.AZ.196.196; 7.AZ.196.223; 7.AZ.196.240; 7.AZ.196.244;7.AZ.196.243; 7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196;7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243; 7.AZ.223.247;7.AZ.240.157; 7.AZ.240.158; 7.AZ.240.196; 7.AZ.240.223; 7.AZ.240.240;7.AZ.240.244; 7.AZ.240.243; 7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158;7.AZ.244.196; 7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243;7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196; 7.AZ.247.223;7.AZ.247.240; 7.AZ.247.244; 7.AZ.247.243; 7.AZ.247.247; Prodrugs of 7.BF7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244;7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223;7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158;7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247;7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223; 7.BF.15.240;7.BF.15.244; 7.BF.15.243; 7.BF.15.247; 7.BF.16.157; 7.BF.16.158;7.BF.16.196; 7.BF.16.223; 7.BF.16.240; 7.BF.16.244; 7.BF.16.243;7.BF.16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196; 7.BF.18.223;7.BF.18.240; 7.BF.18.244; 7.BF.18.243; 7.BF.18.247; 7.BF.26.157;7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240; 7.BF.26.244;7.BF.26.243; 7.BF.26.247; 7.BF.27.157; 7.BF.27.158; 7.BF.27.196;7.BF.27.223; 7.BF.27.240; 7.BF.27.244; 7.BF.27.243; 7.BF.27.247;7.BF.29.157; 7.BF.29.158; 7.BF.29.196; 7.BF.29.223; 7.BF.29.240;7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157; 7.BF.54.158;7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244; 7.BF.54.243;7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196; 7.BF.55.223;7.BF.55.240; 7.BF.55.244; 7.BF.55.243; 7.BF.55.247; 7.BF.56.157;7.BF.56.158; 7.BF.56.196; 7.BF.56.223; 7.BF.56.240; 7.BF.56.244;7.BF.56.243; 7.BF.56.247; 7.BF.157.157; 7.BF.157.158; 7.BF.157.196;7.BF.157.223; 7.BF.157.240; 7.BF.157.244; 7.BF.157.243; 7.BF.157.247;7.BF.196.157; 7.BF.196.158; 7.BF.196.196; 7.BF.196.223; 7.BF.196.240;7.BF.196.244; 7.BF.196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158;7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244; 7.BF.223.243;7.BF.223.247; 7.BF.240.157; 7.BF.240.158; 7.BF.240.196; 7.BF.240.223;7.BF.240.240; 7.BF.240.244; 7.BF.240.243; 7.BF.240.247; 7.BF.244.157;7.BF.244.158; 7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244;7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158; 7.BF.247.196;7.BF.247.223; 7.BF.247.240; 7.BF.247.244; 7.BF.247.243; 7.BF.247.247;Prodrugs of 7.CI 7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223;7.CI.4.240; 7.CI.4.244; 7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158;7.CI.5.196; 7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247;7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244;7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158; 7.CI.15.196;7.CI.15.223; 7.CI.15.240; 7.CI.15.244; 7.CI.15.243; 7.CI.15.247;7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223; 7.CI.16.240;7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157; 7.CI.18.158;7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243;7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223;7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247; 7.CI.27.157;7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240; 7.CI.27.244;7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158; 7.CI.29.196;7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247;7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240;7.CI.54.244; 7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158;7.CI.55.196; 7.CI.55.223; 7.CI.55.240; 7.CI.55.244; 7.CI.55.243;7.CI.55.247; 7.CI.56.157; 7.CI.56.158; 7.CI.56.196; 7.CI.56.223;7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247; 7.CI.157.157;7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240; 7.CI.157.244;7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196;7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243; 7.CI.196.247;7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CI.223.223; 7.CI.223.240;7.CI.223.244; 7.CI.223.243; 7.CI.223.247; 7.CI.240.157; 7.CI.240.158;7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CI.240.244; 7.CI.240.243;7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196; 7.CI.244.223;7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247; 7.CI.247.157;7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244;7.CI.247.243; 7.CI.247.247; Prodrugs of 7.CO 7.CO.4.157; 7.CO.4.158;7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240; 7.CO.5.244;7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158; 7.CO.7.196; 7.CO.7.223;7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247; 7.CO.15.157;7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO.15.244;7.CO.15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196;7.CO.16.223; 7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247;7.CO.18.157; 7.CO.18.158; 7.CO.18.196; 7.CO.18.223; 7.CO.18.240;7.CO.18.244; 7.CO.18.243; 7.CO.18.247; 7.CO.26.157; 7.CO.26.158;7.CO.26.196; 7.CO.26.223; 7.CO.26.240; 7.CO.26.244; 7.CO.26.243;7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223;7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157;7.CO.29.158; 7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244;7.CO.29.243; 7.CO.29.247; 7.CO.54.157; 7.CO.54.158; 7.CO.54.196;7.CO.54.223; 7.CO.54.240; 7.CO.54.244; 7.CO.54.243; 7.CO.54.247;7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223; 7.CO.55.240;7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158;7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243;7.CO.56.247; 7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223;7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157;7.CO.196.158; 7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244;7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196;7.CO.223.223; 7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247;7.CO.240.157; 7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240;7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158;7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243;7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223;7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247; Prodrugs of 8.AH8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244;8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223;8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158;8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247;8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240;8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158;8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243;8.AH.16.247; 8.AH.18.157; 8.AH.18.158; 8.AH.18.196; 8.AH.18.223;8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157;8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244;8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196;8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247;8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240;8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158;8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243;8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223;8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157;8.AH.56.158; 8.AH.56.196; 8.AH.56.223; 8.AH.56.240; 8.AH.56.244;8.AH.56.243; 8.AH.56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196;8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH.157.243; 8.AH.157.247;8.AH.196.157; 8.AH.196.158; 8.AH.196.196; 8.AH.196.223; 8.AH.196.240;8.AH.196.244; 8.AH.196.243; 8.AH.196.247; 8.AH.223.157; 8.AH.223.158;8.AH.223.196; 8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243;8.AH.223.247; 8.AH.240.157; 8.AH.240.158; 8.AH.240.196; 8.AH.240.223;8.AH.240.240; 8.AH.240.244; 8.AH.240.243; 8.AH.240.247; 8.AH.244.157;8.AH.244.158; 8.AH.244.196; 8.AH.244.223; 8.AH.244.240; 8.AH.244.244;8.AH.244.243; 8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196;8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243; 8.AH.247.247;Prodrugs of 8.AJ 8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223;8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158;8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247;8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244;8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157; 8.AJ.15.158; 8.AJ.15.196;8.AJ.15.223; 8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247;8.AJ.16.157; 8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240;8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158;8.AJ.18.196; 8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243;8.AJ.18.247; 8.AJ.26.157; 8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223;8.AJ.26.240; 8.AJ.26.244; 8.AJ.26.243; 8.AJ.26.247; 8.AJ.27.157;8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244;8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196;8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247;8.AJ.54.157; 8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240;8.AJ.54.244; 8.AJ.54.243; 8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158;8.AJ.55.196; 8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243;8.AJ.55.247; 8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196; 8.AJ.56.223;8.AJ.56.240; 8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157;8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244;8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158; 8.AJ.196.196;8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244; 8.AJ.196.243; 8.AJ.196.247;8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240;8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158;8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243;8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223;8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157;8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244;8.AJ.247.243; 8.AJ.247.247; Prodrugs of 8.AN 8.AN.4.157; 8.AN.4.158;8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244; 8.AN.4.243; 8.AN.4.247;8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223; 8.AN.5.240; 8.AN.5.244;8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223;8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157;8.AN.15.158; 8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244;8.AN.15.243; 8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196;8.AN.16.223; 8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247;8.AN.18.157; 8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240;8.AN.18.244; 8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158;8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243;8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223;8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157;8.AN.29.158; 8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244;8.AN.29.243; 8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196;8.AN.54.223; 8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247;8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240;8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158;8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243;8.AN.56.247; 8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223;8.AN.157.240; 8.AN.157.244; 8.AN.157.243; 8.AN.157.247; 8.AN.196.157;8.AN.196.158; 8.AN.196.196; 8.AN.196.223; 8.AN.196.240; 8.AN.196.244;8.AN.196.243; 8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196;8.AN.223.223; 8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247;8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240;8.AN.240.244; 8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158;8.AN.244.196; 8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243;8.AN.244.247; 8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223;8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247; Prodrugs of 8.AP8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244;8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223;8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158;8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247;8.AP.15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240;8.AP.15.244; 8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158;8.AP.16.196; 8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243;8.AP.16.247; 8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223;8.AP.18.240; 8.AP.18.244; 8.AP.18.243; 8.AP.18.247; 8.AP.26.157;8.AP.26.158; 8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244;8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196;8.AP.27.223; 8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247;8.AP.29.157; 8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240;8.AP.29.244; 8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158;8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243;8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223;8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157;8.AP.56.158; 8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244;8.AP.56.243; 8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196;8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243; 8.AP.157.247;8.AP.196.157; 8.AP.196.158; 8.AP.196.196; 8.AP.196.223; 8.AP.196.240;8.AP.196.244; 8.AP.196.243; 8.AP.196.247; 8.AP.223.157; 8.AP.223.158;8.AP.223.196; 8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243;8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196; 8.AP.240.223;8.AP.240.240; 8.AP.240.244; 8.AP.240.243; 8.AP.240.247; 8.AP.244.157;8.AP.244.158; 8.AP.244.196; 8.AP.244.223; 8.AP.244.240; 8.AP.244.244;8.AP.244.243; 8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196;8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243; 8.AP.247.247;Prodrugs of 8.AZ 8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223;8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158;8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247;8.AZ.7.157; 8.AZ.7.158; 8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244;8.AZ.7.243; 8.AZ.7.247; 8.AZ.15.157; 8.AZ.15.158; 8.AZ.15.196;8.AZ.15.223; 8.AZ.15.240; 8.AZ.15.244; 8.AZ.15.243; 8.AZ.15.247;8.AZ.16.157; 8.AZ.16.158; 8.AZ.16.196; 8.AZ.16.223; 8.AZ.16.240;8.AZ.16.244; 8.AZ.16.243; 8.AZ.16.247; 8.AZ.18.157; 8.AZ.18.158;8.AZ.18.196; 8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243;8.AZ.18.247; 8.AZ.26.157; 8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223;8.AZ.26.240; 8.AZ.26.244; 8.AZ.26.243; 8.AZ.26.247; 8.AZ.27.157;8.AZ.27.158; 8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244;8.AZ.27.243; 8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196;8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247;8.AZ.54.157; 8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240;8.AZ.54.244; 8.AZ.54.243; 8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158;8.AZ.55.196; 8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243;8.AZ.55.247; 8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196; 8.AZ.56.223;8.AZ.56.240; 8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157;8.AZ.157.158; 8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244;8.AZ.157.243; 8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158; 8.AZ.196.196;8.AZ.196.223; 8.AZ.196.240; 8.AZ.196.244; 8.AZ.196.243; 8.AZ.196.247;8.AZ.223.157; 8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240;8.AZ.223.244; 8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158;8.AZ.240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ.240.243;8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223;8.AZ.244.240; 8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157;8.AZ.247.158; 8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244;8.AZ.247.243; 8.AZ.247.247; Prodrugs of 8.BF 8.BF.4.157; 8.BF.4.158;8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244; 8.BF.4.243; 8.BF.4.247;8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223; 8.BF.5.240; 8.BF.5.244;8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223;8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF.15.157;8.BF.15.158; 8.BF.15.196; 8.BF.15.223; 8.BF.15.240; 8.BF.15.244;8.BF.15.243; 8.BF.15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196;8.BF.16.223; 8.BF.16.240; 8.BF.16.244; 8.BF.16.243; 8.BF.16.247;8.BF.18.157; 8.BF.18.158; 8.BF.18.196; 8.BF.18.223; 8.BF.18.240;8.BF.18.244; 8.BF.18.243; 8.BF.18.247; 8.BF.26.157; 8.BF.26.158;8.BF.26.196; 8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243;8.BF.26.247; 8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223;8.BF.27.240; 8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157;8.BF.29.158; 8.BF.29.196; 8.BF.29.223; 8.BF.29.240; 8.BF.29.244;8.BF.29.243; 8.BF.29.247; 8.BF.54.157; 8.BF.54.158; 8.BF.54.196;8.BF.54.223; 8.BF.54.240; 8.BF.54.244; 8.BF.54.243; 8.BF.54.247;8.BF.55.157; 8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240;8.BF.55.244; 8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158;8.BF.56.196; 8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243;8.BF.56.247; 8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223;8.BF.157.240; 8.BF.157.244; 8.BF.157.243; 8.BF.157.247; 8.BF.196.157;8.BF.196.158; 8.BF.196.196; 8.BF.196.223; 8.BF.196.240; 8.BF.196.244;8.BF.196.243; 8.BF.196.247; 8.BF.223.157; 8.BF.223.158; 8.BF.223.196;8.BF.223.223; 8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247;8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223; 8.BF.240.240;8.BF.240.244; 8.BF.240.243; 8.BF.240.247; 8.BF.244.157; 8.BF.244.158;8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243;8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223;8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247; Prodrugs of 8.CI8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244;8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223;8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI.7.157; 8.CI.7.158;8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247;8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240;8.CI.15.244; 8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8.CI.16.158;8.CI.16.196; 8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8.CI.16.243;8.CI.16.247; 8.CI.18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223;8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157;8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244;8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196;8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247;8.CI.29.157; 8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240;8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158;8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243;8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223;8.CI.55.240; 8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157;8.CI.56.158; 8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244;8.CI.56.243; 8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196;8.CI.157.223; 8.CI.157.240; 8.CI.157.244; 8.CI.157.243; 8.CI.157.247;8.CI.196.157; 8.CI.196.158; 8.CI.196.196; 8.CI.196.223; 8.CI.196.240;8.CI.196.244; 8.CI.196.243; 8.CI.196.247; 8.CI.223.157; 8.CI.223.158;8.CI.223.196; 8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243;8.CI.223.247; 8.CI.240.157; 8.CI.240.158; 8.CI.240.196; 8.CI.240.223;8.CI.240.240; 8.CI.240.244; 8.CI.240.243; 8.CI.240.247; 8.CI.244.157;8.CI.244.158; 8.CI.244.196; 8.CI.244.223; 8.CI.244.240; 8.CI.244.244;8.CI.244.243; 8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196;8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243; 8.CI.247.247;Prodrugs of 8.CO 8.CO.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223;8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158;8.CO.5.196; 8.CO.5.223; 8.CO.5.240; 8.CO.5.244; 8.CO.5.243; 8.CO.5.247;8.CO.7.157; 8.CO.7.158; 8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244;8.CO.7.243; 8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.196;8.CO.15.223; 8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247;8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240;8.CO.16.244; 8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158;8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243;8.CO.18.247; 8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223;8.CO.26.240; 8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157;8.CO.27.158; 8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244;8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196;8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247;8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240;8.CO.54.244; 8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158;8.CO.55.196; 8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243;8.CO.55.247; 8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223;8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157;8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244;8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158; 8.CO.196.196;8.CO.196.223; 8.CO.196.240; 8.CO.196.244; 8.CO.196.243; 8.CO.196.247;8.CO.223.157; 8.CO.223.158; 8.CO.223.196; 8.CO.223.223; 8.CO.223.240;8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.CO.240.158;8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244; 8.CO.240.243;8.CO.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196; 8.CO.244.223;8.CO.244.240; 8.CO.244.244; 8.CO.244.243; 8.CO.244.247; 8.CO.247.157;8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244;8.CO.247.243; 8.CO.247.247; Prodrugs of 9.AH 9.AH.4.157; 9.AH.4.158;9.AH.4.196; 9.AH.4.223; 9.AH.4.240; 9.AH.4.244; 9.AH.4.243; 9.AH.4.247;9.AH.5.157; 9.AH.5.158; 9.AH.5.196; 9.AH.5.223; 9.AH.5.240; 9.AH.5.244;9.AH.5.243; 9.AH.5.247; 9.AH.7.157; 9.AH.7.158; 9.AH.7.196; 9.AH.7.223;9.AH.7.240; 9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH.15.157;9.AH.15.158; 9.AH.15.196; 9.AH.15.223; 9.AH.15.240; 9.AH.15.244;9.AH.15.243; 9.AH.15.247; 9.AH.16.157; 9.AH.16.158; 9.AH.16.196;9.AH.16.223; 9.AH.16.240; 9.AH.16.244; 9.AH.16.243; 9.AH.16.247;9.AH.18.157; 9.AH.18.158; 9.AH.18.196; 9.AH.18.223; 9.AH.18.240;9.AH.18.244; 9.AH.18.243; 9.AH.18.247; 9.AH.26.157; 9.AH.26.158;9.AH.26.196; 9.AH.26.223; 9.AH.26.240; 9.AH.26.244; 9.AH.26.243;9.AH.26.247; 9.AH.27.157; 9.AH.27.158; 9.AH.27.196; 9.AH.27.223;9.AH.27.240; 9.AH.27.244; 9.AH.27.243; 9.AH.27.247; 9.AH.29.157;9.AH.29.158; 9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244;9.AH.29.243; 9.AH.29.247; 9.AH.54.157; 9.AH.54.158; 9.AH.54.196;9.AH.54.223; 9.AH.54.240; 9.AH.54.244; 9.AH.54.243; 9.AH.54.247;9.AH.55.157; 9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240;9.AH.55.244; 9.AH.55.243; 9.AH.55.247; 9.AH.56.157; 9.AH.56.158;9.AH.56.196; 9.AH.56.223; 9.AH.56.240; 9.AH.56.244; 9.AH.56.243;9.AH.56.247; 9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH.157.223;9.AH.157.240; 9.AH.157.244; 9.AH.157.243; 9.AH.157.247; 9.AH.196.157;9.AH.196.158; 9.AH.196.196; 9.AH.196.223; 9.AH.196.240; 9.AH.196.244;9.AH.196.243; 9.AH.196.247; 9.AH.223.157; 9.AH.223.158; 9.AH.223.196;9.AH.223.223; 9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247;9.AH.240.157; 9.AH.240.158; 9.AH.240.196; 9.AH.240.223; 9.AH.240.240;9.AH.240.244; 9.AH.240.243; 9.AH.240.247; 9.AH.244.157; 9.AH.244.158;9.AH.244.196; 9.AH.244.223; 9.AH.244.240; 9.AH.244.244; 9.AH.244.243;9.AH.244.247; 9.AH.247.157; 9.AH.247.158; 9.AH.247.196; 9.AH.247.223;9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247; Prodrugs of 9.AJ9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244;9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223;9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158;9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247;9.AJ.15.157; 9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; 9.AJ.15.240;9.AJ.15.244; 9.AJ.15.243; 9.AJ.15.247; 9.AJ.16.157; 9.AJ.16.158;9.AJ.16.196; 9.AJ.16.223; 9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243;9.AJ.16.247; 9.AJ.18.157; 9.AJ.18.158; 9.AJ.18.196; 9.AJ.18.223;9.AJ.18.240; 9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247; 9.AJ.26.157;9.AJ.26.158; 9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244;9.AJ.26.243; 9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196;9.AJ.27.223; 9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247;9.AJ.29.157; 9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240;9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247; 9.AJ.54.157; 9.AJ.54.158;9.AJ.54.196; 9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244; 9.AJ.54.243;9.AJ.54.247; 9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223;9.AJ.55.240; 9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ.56.157;9.AJ.56.158; 9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244;9.AJ.56.243; 9.AJ.56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196;9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ.157.243; 9.AJ.157.247;9.AJ.196.157; 9.AJ.196.158; 9.AJ.196.196; 9.AJ.196.223; 9.AJ.196.240;9.AJ.196.244; 9.AJ.196.243; 9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158;9.AJ.223.196; 9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243;9.AJ.223.247; 9.AJ.240.157; 9.AJ.240.158; 9.AJ.240.196; 9.AJ.240.223;9.AJ.240.240; 9.AJ.240.244; 9.AJ.240.243; 9.AJ.240.247; 9.AJ.244.157;9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244;9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ.247.196;9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243; 9.AJ.247.247;Prodrugs of 9.AN 9.AN.4.157; 9.AN.4.158; 9.AN.4.196; 9.AN.4.223;9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158;9.AN.5.196; 9.AN.5.223; 9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247;9.AN.7.157; 9.AN.7.158; 9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244;9.AN.7.243; 9.AN.7.247; 9.AN.15.157; 9.AN.15.158; 9.AN.15.196;9.AN.15.223; 9.AN.15.240; 9.AN.15.244; 9.AN.15.243; 9.AN.15.247;9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240;9.AN.16.244; 9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158;9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243;9.AN.18.247; 9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223;9.AN.26.240; 9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157;9.AN.27.158; 9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244;9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196;9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247;9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240;9.AN.54.244; 9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158;9.AN.55.196; 9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243;9.AN.55.247; 9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223;9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157;9.AN.157.158; 9.AN.157.196; 9.AN.157.223; 9.AN.157.240; 9.AN.157.244;9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158; 9.AN.196.196;9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243; 9.AN.196.247;9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223; 9.AN.223.240;9.AN.223.244; 9.AN.223.243; 9.AN.223.247; 9.AN.240.157; 9.AN.240.158;9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244; 9.AN.240.243;9.AN.240.247; 9.AN.244.157; 9.AN.244.158; 9.AN.244.196; 9.AN.244.223;9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247; 9.AN.247.157;9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244;9.AN.247.243; 9.AN.247.247; Prodrugs of 9.AP 9.AP.4.157; 9.AP.4.158;9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244; 9.AP.4.243; 9.AP.4.247;9.AP.5.157; 9.AP.5.158; 9.AP.5.196; 9.AP.5.223; 9.AP.5.240; 9.AP.5.244;9.AP.5.243; 9.AP.5.247; 9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223;9.AP.7.240; 9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157;9.AP.15.158; 9.AP.15.196; 9.AP.15.223; 9.AP.15.240; 9.AP.15.244;9.AP.15.243; 9.AP.15.247; 9.AP.16.157; 9.AP.16.158; 9.AP.16.196;9.AP.16.223; 9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247;9.AP.18.157; 9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240;9.AP.18.244; 9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158;9.AP.26.196; 9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243;9.AP.26.247; 9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223;9.AP.27.240; 9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157;9.AP.29.158; 9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244;9.AP.29.243; 9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196;9.AP.54.223; 9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247;9.AP.55.157; 9.AP.55.158; 9.AP.55.196; 9.AP.55.223; 9.AP.55.240;9.AP.55.244; 9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158;9.AP.56.196; 9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243;9.AP.56.247; 9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223;9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247; 9.AP.196.157;9.AP.196.158; 9.AP.196.196; 9.AP.196.223; 9.AP.196.240; 9.AP.196.244;9.AP.196.243; 9.AP.196.247; 9.AP.223.157; 9.AP.223.158; 9.AP.223.196;9.AP.223.223; 9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247;9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223; 9.AP.240.240;9.AP.240.244; 9.AP.240.243; 9.AP.240.247; 9.AP.244.157; 9.AP.244.158;9.AP.244.196; 9.AP.244.223; 9.AP.244.240; 9.AP.244.244; 9.AP.244.243;9.AP.244.247; 9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223;9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247; Prodrugs of 9.AZ9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240; 9.AZ.4.244;9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223;9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158;9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247;9.AZ.15.157; 9.AZ.15.158; 9.AZ.15.196; 9.AZ.15.223; 9.AZ.15.240;9.AZ.15.244; 9.AZ.15.243; 9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158;9.AZ.16.196; 9.AZ.16.223; 9.AZ.16.240; 9.AZ.16.244; 9.AZ.16.243;9.AZ.16.247; 9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196; 9.AZ.18.223;9.AZ.18.240; 9.AZ.18.244; 9.AZ.18.243; 9.AZ.18.247; 9.AZ.26.157;9.AZ.26.158; 9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244;9.AZ.26.243; 9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196;9.AZ.27.223; 9.AZ.27.240; 9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247;9.AZ.29.157; 9.AZ.29.158; 9.AZ.29.196; 9.AZ.29.223; 9.AZ.29.240;9.AZ.29.244; 9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157; 9.AZ.54.158;9.AZ.54.196; 9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243;9.AZ.54.247; 9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223;9.AZ.55.240; 9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157;9.AZ.56.158; 9.AZ.56.196; 9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244;9.AZ.56.243; 9.AZ.56.247; 9.AZ.157.157; 9.AZ.157.158; 9.AZ.157.196;9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243; 9.AZ.157.247;9.AZ.196.157; 9.AZ.196.158; 9.AZ.196.196; 9.AZ.196.223; 9.AZ.196.240;9.AZ.196.244; 9.AZ.196.243; 9.AZ.196.247; 9.AZ.223.157; 9.AZ.223.158;9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243;9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196; 9.AZ.240.223;9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243; 9.AZ.240.247; 9.AZ.244.157;9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244;9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196;9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243; 9.AZ.247.247;Prodrugs of 9.BF 9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223;9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158;9.BF.5.196; 9.BF.5.223; 9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247;9.BF.7.157; 9.BF.7.158; 9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244;9.BF.7.243; 9.BF.7.247; 9.BF.15.157; 9.BF.15.158; 9.BF.15.196;9.BF.15.223; 9.BF.15.240; 9.BF.15.244; 9.BF.15.243; 9.BF.15.247;9.BF.16.157; 9.BF.16.158; 9.BF.16.196; 9.BF.16.223; 9.BF.16.240;9.BF.16.244; 9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158;9.BF.18.196; 9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243;9.BF.18.247; 9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223;9.BF.26.240; 9.BF.26.244; 9.BF.26.243; 9.BF.26.247; 9.BF.27.157;9.BF.27.158; 9.BF.27.196; 9.BF.27.223; 9.BF.27.240; 9.BF.27.244;9.BF.27.243; 9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196;9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247;9.BF.54.157; 9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240;9.BF.54.244; 9.BF.54.243; 9.BF.54.247; 9.BF.55.157; 9.BF.55.158;9.BF.55.196; 9.BF.55.223; 9.BF.55.240; 9.BF.55.244; 9.BF.55.243;9.BF.55.247; 9.BF.56.157; 9.BF.56.158; 9.BF.56.196; 9.BF.56.223;9.BF.56.240; 9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157;9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244;9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196;9.BF.196.223; 9.BF.196.240; 9.BF.196.244; 9.BF.196.243; 9.BF.196.247;9.BF.223.157; 9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240;9.BF.223.244; 9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158;9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243;9.BF.240.247; 9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223;9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157;9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244;9.BF.247.243; 9.BF.247.247; Prodrugs of 9.CI 9.CI.4.157; 9.CI.4.158;9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247;9.CI.5.157; 9.CI.5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244;9.CI.5.243; 9.CI.5.247; 9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223;9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157;9.CI.15.158; 9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244;9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196;9.CI.16.223; 9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247;9.CI.18.157; 9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240;9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158;9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243;9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223;9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157;9.CI.29.158; 9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244;9.CI.29.243; 9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196;9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.247;9.CI.55.157; 9.CI.55.158; 9.CI.55.196; 9.CI.55.223; 9.CI.55.240;9.CI.55.244; 9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158;9.CI.56.196; 9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243;9.CI.56.247; 9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223;9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247; 9.CI.196.157;9.CI.196.158; 9.CI.196.196; 9.CI.196.223; 9.CI.196.240; 9.CI.196.244;9.CI.196.243; 9.CI.196.247; 9.CI.223.157; 9.CI.223.158; 9.CI.223.196;9.CI.223.223; 9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247;9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223; 9.CI.240.240;9.CI.240.244; 9.CI.240.243; 9.CI.240.247; 9.CI.244.157; 9.CI.244.158;9.CI.244.196; 9.CI.244.223; 9.CI.244.240; 9.CI.244.244; 9.CI.244.243;9.CI.244.247; 9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223;9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247; Prodrugs of 9.CO9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240; 9.CO.4.244;9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223;9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158;9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247;9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240;9.CO.15.244; 9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158;9.CO.16.196; 9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243;9.CO.16.247; 9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223;9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157;9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244;9.CO.26.243; 9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196;9.CO.27.223; 9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247;9.CO.29.157; 9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240;9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158;9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243;9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223;9.CO.55.240; 9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157;9.CO.56.158; 9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244;9.CO.56.243; 9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196;9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243; 9.CO.157.247;9.CO.196.157; 9.CO.196.158; 9.CO.196.196; 9.CO.196.223; 9.CO.196.240;9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157; 9.CO.223.158;9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243;9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196; 9.CO.240.223;9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157;9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.CO.244.244;9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196;9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;Prodrugs of 10.AH 10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223;10.AH.4.240; 10.AH.4.244; 10.AH.4.243; 10.AH.4.247; 10.AH.5.157;10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244;10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH.7.158; 10.AH.7.196;10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247;10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH.15.223; 10.AH.15.240;10.AH.15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10.AH.16.158;10.AH.16.196; 10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243;10.AH.16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196; 10.AH.18.223;10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157;10.AH.26.158; 10.AH.26.196; 10.AH.26.223; 10.AH.26.240; 10.AH.26.244;10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196;10.AH.27.223; 10.AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247;10.AH.29.157; 10.AH.29.158; 10.AH.29.196; 10.AH.29.223; 10.AH.29.240;10.AH.29.244; 10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158;10.AH.54.196; 10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243;10.AH.54.247; 10.AH.55.157; 10.AH.55.158; 10.AH.55.196; 10.AH.55.223;10.AH.55.240; 10.AH.55.244; 10.AH.55.243; 10.AH.55.247; 10.AH.56.157;10.AH.56.158; 10.AH.56.196; 10.AH.56.223; 10.AH.56.240; 10.AH.56.244;10.AH.56.243; 10.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH.157.196;10.AH.157.223; 10.AH.157.240; 10.AH.157.244; 10.AH.157.243;10.AH.157.247; 10.AH.196.157; 10.AH.196.158; 10.AH.196.196;10.AH.196.223; 10.AH.196.240; 10.AH.196.244; 10.AH.196.243;10.AH.196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196;10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243;10.AH.223.247; 10.AH.240.157; 10.AH.240.158; 10.AH.240.196;10.AH.240.223; 10.AH.240.240; 10.AH.240.244; 10.AH.240.243;10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196;10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243;10.AH.244.247; 10.AH.247.157; 10.AH.247.158; 10.AH.247.196;10.AH.247.223; 10.AH.247.240; 10.AH.247.244; 10.AH.247.243;10.AH.247.247; Prodrugs of 10.AJ 10.AJ.4.157; 10.AJ.4.158; 10.AJ.4.196;10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; 10.AJ.4.243; 10.AJ.4.247;10.AJ.5.157; 10.AJ.5.158; 10.AJ.5.196; 10.AJ.5.223; 10.AJ.5.240;10.AJ.5.244; 10.AJ.5.243; 10.AJ.5.247; 10.AJ.7.157; 10.AJ.7.158;10.AJ.7.196; 10.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244; 10.AJ.7.243;10.AJ.7.247; 10.AJ.15.157; 10.AJ.15.158; 10.AJ.15.196; 10.AJ.15.223;10.AJ.15.240; 10.AJ.15.244; 10.AJ.15.243; 10.AJ.15.247; 10.AJ.16.157;10.AJ.16.158; 10.AJ.16.196; 10.AJ.16.223; 10.AJ.16.240; 10.AJ.16.244;10.AJ.16.243; 10.AJ.16.247; 10.AJ.18.157; 10.AJ.18.158; 10.AJ.18.196;10.AJ.18.223; 10.AJ.18.240; 10.AJ.18.244; 10.AJ.18.243; 10.AJ.18.247;10.AJ.26.157; 10.AJ.26.158; 10.AJ.26.196; 10.AJ.26.223; 10.AJ.26.240;10.AJ.26.244; 10.AJ.26.243; 10.AJ.26.247; 10.AJ.27.157; 10.AJ.27.158;10.AJ.27.196; 10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243;10.AJ.27.247; 10.AJ.29.157; 10.AJ.29.158; 10.AJ.29.196; 10.AJ.29.223;10.AJ.29.240; 10.AJ.29.244; 10.AJ.29.243; 10.AJ.29.247; 10.AJ.54.157;10.AJ.54.158; 10.AJ.54.196; 10.AJ.54.223; 10.AJ.54.240; 10.AJ.54.244;10.AJ.54.243; 10.AJ.54.247; 10.AJ.55.157; 10.AJ.55.158; 10.AJ.55.196;10.AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10.AJ.55.243; 10.AJ.55.247;10.AJ.56.157; 10.AJ.56.158; 10.AJ.56.196; 10.AJ.56.223; 10.AJ.56.240;10.AJ.56.244; 10.AJ.56.243; 10.AJ.56.247; 10.AJ.157.157; 10.AJ.157.158;10.AJ.157.196; 10.AJ.157.223; 10.AJ.157.240; 10.AJ.157.244;10.AJ.157.243; 10.AJ.157.247; 10.AJ.196.157; 10.AJ.196.158;10.AJ.196.196; 10.AJ.196.223; 10.AJ.196.240; 10.AJ.196.244;10.AJ.196.243; 10.AJ.196.247; 10.AJ.223.157; 10.AJ.223.158;10.AJ.223.196; 10.AJ.223.223; 10.AJ.223.240; 10.AJ.223.244;10.AJ.223.243; 10.AJ.223.247; 10.AJ.240.157; 10.AJ.240.158;10.AJ.240.196; 10.AJ.240.223; 10.AJ.240.240; 10.AJ.240.244;10.AJ.240.243; 10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158;10.AJ.244.196; 10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244;10.AJ.244.243; 10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158;10.AJ.247.196; 10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244;10.AJ.247.243; 10.AJ.247.247; Prodrugs of 10.AN 10.AN.4.157;10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244;10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196;10.AN.5.223; 10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247;10.AN.7.157; 10.AN.7.158; 10.AN.7.196; 10.AN.7.223; 10.AN.7.240;10.AN.7.244; 10.AN.7.243; 10.AN.7.247; 10.AN.15.157; 10.AN.15.158;10.AN.15.196; 10.AN.15.223; 10.AN.15.240; 10.AN.15.244; 10.AN.15.243;10.AN.15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196; 10.AN.16.223;10.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247; 10.AN.18.157;10.AN.18.158; 10.AN.18.196; 10.AN.18.223; 10.AN.18.240; 10.AN.18.244;10.AN.18.243; 10.AN.18.247; 10.AN.26.157; 10.AN.26.158; 10.AN.26.196;10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243; 10.AN.26.247;10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223; 10.AN.27.240;10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157; 10.AN.29.158;10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243;10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196; 10.AN.54.223;10.AN.54.240; 10.AN.54.244; 10.AN.54.243; 10.AN.54.247; 10.AN.55.157;10.AN.55.158; 10.AN.55.196; 10.AN.55.223; 10.AN.55.240; 10.AN.55.244;10.AN.55.243; 10.AN.55.247; 10.AN.56.157; 10.AN.56.158; 10.AN.56.196;10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243; 10.AN.56.247;10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN.157.223;10.AN.157.240; 10.AN.157.244; 10.AN.157.243; 10.AN.157.247;10.AN.196.157; 10.AN.196.158; 10.AN.196.196; 10.AN.196.223;10.AN.196.240; 10.AN.196.244; 10.AN.196.243; 10.AN.196.247;10.AN.223.157; 10.AN.223.158; 10.AN.223.196; 10.AN.223.223;10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247;10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223;10.AN.240.240; 10.AN.240.244; 10.AN.240.243; 10.AN.240.247;10.AN.244.157; 10.AN.244.158; 10.AN.244.196; 10.AN.244.223;10.AN.244.240; 10.AN.244.244; 10.AN.244.243; 10.AN.244.247;10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223;10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247; Prodrugs of10.AP 10.AP.4.157; 10.AP.4.158; 10.AP.4.196; 10.AP.4.223; 10.AP.4.240;10.AP.4.244; 10.AP.4.243; 10.AP.4.247; 10.AP.5.157; 10.AP.5.158;10.AP.5.196; 10.AP.5.223; 10.AP.5.240; 10.AP.5.244; 10.AP.5.243;10.AP.5.247; 10.AP.7.157; 10.AP.7.158; 10.AP.7.196; 10.AP.7.223;10.AP.7.240; 10.AP.7.244; 10.AP.7.243; 10.AP.7.247; 10.AP.15.157;10.AP.15.158; 10.AP.15.196; 10.AP.15.223; 10.AP.15.240; 10.AP.15.244;10.AP.15.243; 10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196;10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243; 10.AP.16.247;10.AP.18.157; 10.AP.18.158; 10.AP.18.196; 10.AP.18.223; 10.AP.18.240;10.AP.18.244; 10.AP.18.243; 10.AP.18.247; 10.AP.26.157; 10.AP.26.158;10.AP.26.196; 10.AP.26.223; 10.AP.26.240; 10.AP.26.244; 10.AP.26.243;10.AP.26.247; 10.AP.27.157; 10.AP.27.158; 10.AP.27.196; 10.AP.27.223;10.AP.27.240; 10.AP.27.244; 10.AP.27.243; 10.AP.27.247; 10.AP.29.157;10.AP.29.158; 10.AP.29.196; 10.AP.29.223; 10.AP.29.240; 10.AP.29.244;10.AP.29.243; 10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196;10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243; 10.AP.54.247;10.AP.55.157; 10.AP.55.158; 10.AP.55.196; 10.AP.55.223; 10.AP.55.240;10.AP.55.244; 10.AP.55.243; 10.AP.55.247; 10.AP.56.157; 10.AP.56.158;10.AP.56.196; 10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243;10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196;10.AP.157.223; 10.AP.157.240; 10.AP.157.244; 10.AP.157.243;10.AP.157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196;10.AP.196.223; 10.AP.196.240; 10.AP.196.244; 10.AP.196.243;10.AP.196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196;10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243;10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196;10.AP.240.223; 10.AP.240.240; 10.AP.240.244; 10.AP.240.243;10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196;10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243;10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196;10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243;10.AP.247.247; Prodrugs of 10.AZ 10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196;10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243; 10.AZ.4.247;10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223; 10.AZ.5.240;10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158;10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243;10.AZ.7.247; 10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196; 10.AZ.15.223;10.AZ.15.240; 10.AZ.15.244; 10.AZ.15.243; 10.AZ.15.247; 10.AZ.16.157;10.AZ.16.158; 10.AZ.16.196; 10.AZ.16.223; 10.AZ.16.240; 10.AZ.16.244;10.AZ.16.243; 10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196;10.AZ.18.223; 10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243; 10.AZ.18.247;10.AZ.26.157; 10.AZ.26.158; 10.AZ.26.196; 10.AZ.26.223; 10.AZ.26.240;10.AZ.26.244; 10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158;10.AZ.27.196; 10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243;10.AZ.27.247; 10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196; 10.AZ.29.223;10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; 10.AZ.54.157;10.AZ.54.158; 10.AZ.54.196; 10.AZ.54.223; 10.AZ.54.240; 10.AZ.54.244;10.AZ.54.243; 10.AZ.54.247; 10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196;10.AZ.55.223; 10.AZ.55.240; 10.AZ.55.244; 10.AZ.55.243; 10.AZ.55.247;10.AZ.56.157; 10.AZ.56.158; 10.AZ.56.196; 10.AZ.56.223; 10.AZ.56.240;10.AZ.56.244; 10.AZ.56.243; 10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158;10.AZ.157.196; 10.AZ.157.223; 10.AZ.157.240; 10.AZ.157.244;10.AZ.157.243; 10.AZ.157.247; 10.AZ.196.157; 10.AZ.196.158;10.AZ.196.196; 10.AZ.196.223; 10.AZ.196.240; 10.AZ.196.244;10.AZ.196.243; 10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158;10.AZ.223.196; 10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244;10.AZ.223.243; 10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158;10.AZ.240.196; 10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244;10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158;10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244;10.AZ.244.243; 10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158;10.AZ.247.196; 10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244;10.AZ.247.243; 10.AZ.247.247; Prodrugs of 10.BF 10.BF.4.157;10.BF.4.158; 10.BF.4.196; 10.BF.4.223; 10.BF.4.240; 10.BF.4.244;10.BF.4.243; 10.BF.4.247; 10.BF.5.157; 10.BF.5.158; 10.BF.5.196;10.BF.5.223; 10.BF.5.240; 10.BF.5.244; 10.BF.5.243; 10.BF.5.247;10.BF.7.157; 10.BF.7.158; 10.BF.7.196; 10.BF.7.223; 10.BF.7.240;10.BF.7.244; 10.BF.7.243; 10.BF.7.247; 10.BF.15.157; 10.BF.15.158;10.BF.15.196; 10.BF.15.223; 10.BF.15.240; 10.BF.15.244; 10.BF.15.243;10.BF.15.247; 10.BF.16.157; 10.BF.16.158; 10.BF.16.196; 10.BF.16.223;10.BF.16.240; 10.BF.16.244; 10.BF.16.243; 10.BF.16.247; 10.BF.18.157;10.BF.18.158; 10.BF.18.196; 10.BF.18.223; 10.BF.18.240; 10.BF.18.244;10.BF.18.243; 10.BF.18.247; 10.BF.26.157; 10.BF.26.158; 10.BF.26.196;10.BF.26.223; 10.BF.26.240; 10.BF.26.244; 10.BF.26.243; 10.BF.26.247;10.BF.27.157; 10.BF.27.158; 10.BF.27.196; 10.BF.27.223; 10.BF.27.240;10.BF.27.244; 10.BF.27.243; 10.BF.27.247; 10.BF.29.157; 10.BF.29.158;10.BF.29.196; 10.BF.29.223; 10.BF.29.240; 10.BF.29.244; 10.BF.29.243;10.BF.29.247; 10.BF.54.157; 10.BF.54.158; 10.BF.54.196; 10.BF.54.223;10.BF.54.240; 10.BF.54.244; 10.BF.54.243; 10.BF.54.247; 10.BF.55.157;10.BF.55.158; 10.BF.55.196; 10.BF.55.223; 10.BF.55.240; 10.BF.55.244;10.BF.55.243; 10.BF.55.247; 10.BF.56.157; 10.BF.56.158; 10.BF.56.196;10.BF.56.223; 10.BF.56.240; 10.BF.56.244; 10.BF.56.243; 10.BF.56.247;10.BF.157.157; 10.BF.157.158; 10.BF.157.196; 10.BF.157.223;10.BF.157.240; 10.BF.157.244; 10.BF.157.243; 10.BF.157.247;10.BF.196.157; 10.BF.196.158; 10.BF.196.196; 10.BF.196.223;10.BF.196.240; 10.BF.196.244; 10.BF.196.243; 10.BF.196.247;10.BF.223.157; 10.BF.223.158; 10.BF.223.196; 10.BF.223.223;10.BF.223.240; 10.BF.223.244; 10.BF.223.243; 10.BF.223.247;10.BF.240.157; 10.BF.240.158; 10.BF.240.196; 10.BF.240.223;10.BF.240.240; 10.BF.240.244; 10.BF.240.243; 10.BF.240.247;10.BF.244.157; 10.BF.244.158; 10.BF.244.196; 10.BF.244.223;10.BF.244.240; 10.BF.244.244; 10.BF.244.243; 10.BF.244.247;10.BF.247.157; 10.BF.247.158; 10.BF.247.196; 10.BF.247.223;10.BF.247.240; 10.BF.247.244; 10.BF.247.243; 10.BF.247.247; Prodrugs of10.CI 10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240;10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158;10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243;10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223;10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157;10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240; 10.CI.15.244;10.CI.15.243; 10.CI.15.247; 10.CI.16.157; 10.CI.16.158; 10.CI.16.196;10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243; 10.CI.16.247;10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223; 10.CI.18.240;10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157; 10.CI.26.158;10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243;10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223;10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157;10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244;10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196;10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247;10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240;10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158;10.CI.56.196; 10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243;10.CI.56.247; 10.CI.157.157; 10.CI.157.158; 10.CI.157.196;10.CI.157.223; 10.CI.157.240; 10.CI.157.244; 10.CI.157.243;10.CI.157.247; 10.CI.196.157; 10.CI.196.158; 10.CI.196.196;10.CI.196.223; 10.CI.196.240; 10.CI.196.244; 10.CI.196.243;10.CI.196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196;10.CI.223.223; 10.CI.223.240; 10.CI.223.244; 10.CI.223.243;10.CI.223.247; 10.CI.240.157; 10.CI.240.158; 10.CI.240.196;10.CI.240.223; 10.CI.240.240; 10.CI.240.244; 10.CI.240.243;10.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196;10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243;10.CI.244.247; 10.CI.247.157; 10.CI.247.158; 10.CI.247.196;10.CI.247.223; 10.CI.247.240; 10.CI.247.244; 10.CI.247.243;10.CI.247.247; Prodrugs of 10.CO 10.CO.4.157; 10.CO.4.158; 10.CO.4.196;10.CO.4.223; 10.CO.4.240; 10.CO.4.244; 10.CO.4.243; 10.CO.4.247;10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223; 10.CO.5.240;10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158;10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243;10.CO.7.247; 10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO.15.223;10.CO.15.240; 10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157;10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.CO.16.240; 10.CO.16.244;10.CO.16.243; 10.CO.16.247; 10.CO.18.157; 10.CO.18.158; 10.CO.18.196;10.CO.18.223; 10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247;10.CO.26.157; 10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240;10.CO.26.244; 10.CO.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158;10.CO.27.196; 10.CO.27.223; 10.CO.27.240; 10.CO.27.244; 10.CO.27.243;10.CO.27.247; 10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223;10.CO.29.240; 10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157;10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244;10.CO.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196;10.CO.55.223; 10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247;10.CO.56.157; 10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240;10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158;10.CO.157.196; 10.CO.157.223; 10.CO.157.240; 10.CO.157.244;10.CO.157.243; 10.CO.157.247; 10.CO.196.157; 10.CO.196.158;10.CO.196.196; 10.CO.196.223; 10.CO.196.240; 10.CO.196.244;10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158;10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244;10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.CO.240.158;10.CO.240.196; 10.CO.240.223; 10.CO.240.240; 10.CO.240.244;10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158;10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244;10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158;10.CO.247.196; 10.CO.247.223; 10.CO.247.240; 10.CO.247.244;10.CO.247.243; 10.CO.247.247; Prodrugs of 11.AH 11.AH.4.157;11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240; 11.AH.4.244;11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158; 11.AH.5.196;11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247;11.AH.7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223; 11.AH.7.240;11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH.15.157; 11.AH.15.158;11.AH.15.196; 11.AH.15.223; 11.AH.15.240; 11.AH.15.244; 11.AH.15.243;11.AH.15.247; 11.AH.16.157; 11.AH.16.158; 11.AH.16.196; 11.AH.16.223;11.AH.16.240; 11.AH.16.244; 11.AH.16.243; 11.AH.16.247; 11.AH.18.157;11.AH.18.158; 11.AH.18.196; 11.AH.18.223; 11.AH.18.240; 11.AH.18.244;11.AH.18.243; 11.AH.18.247; 11.AH.26.157; 11.AH.26.158; 11.AH.26.196;11.AH.26.223; 11.AH.26.240; 11.AH.26.244; 11.AH.26.243; 11.AH.26.247;11.AH.27.157; 11.AH.27.158; 11.AH.27.196; 11.AH.27.223; 11.AH.27.240;11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157; 11.AH.29.158;11.AH.29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244; 11.AH.29.243;11.AH.29.247; 11.AH.54.157; 11.AH.54.158; 11.AH.54.196; 11.AH.54.223;11.AH.54.240; 11.AH.54.244; 11.AH.54.243; 11.AH.54.247; 11.AH.55.157;11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240; 11.AH.55.244;11.AH.55.243; 11.AH.55.247; 11.AH.56.157; 11.AH.56.158; 11.AH.56.196;11.AH.56.223; 11.AH.56.240; 11.AH.56.244; 11.AH.56.243; 11.AH.56.247;11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223;11.AH.157.240; 11.AH.157.244; 11.AH.157.243; 11.AH.157.247;11.AH.196.157; 11.AH.196.158; 11.AH.196.196; 11.AH.196.223;11.AH.196.240; 11.AH.196.244; 11.AH.196.243; 11.AH.196.247;11.AH.223.157; 11.AH.223.158; 11.AH.223.196; 11.AH.223.223;11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247;11.AH.240.157; 11.AH.240.158; 11.AH.240.196; 11.AH.240.223;11.AH.240.240; 11.AH.240.244; 11.AH.240.243; 11.AH.240.247;11.AH.244.157; 11.AH.244.158; 11.AH.244.196; 11.AH.244.223;11.AH.244.240; 11.AH.244.244; 11.AH.244.243; 11.AH.244.247;11.AH.247.157; 11.AH.247.158; 11.AH.247.196; 11.AH.247.223;11.AH.247.240; 11.AH.247.244; 11.AH.247.243; 11.AH.247.247; Prodrugs of11.AJ 11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240;11.AJ.4.244; 11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158;11.AJ.5.196; 11.AJ.5.223; 11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243;11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158; 11.AJ.7.196; 11.AJ.7.223;11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247; 11.AJ.15.157;11.AJ.15.158; 11.AJ.15.196; 11.AJ.15.223; 11.AJ.15.240; 11.AJ.15.244;11.AJ.15.243; 11.AJ.15.247; 11.AJ.16.157; 11.AJ.16.158; 11.AJ.16.196;11.AJ.16.223; 11.AJ.16.240; 11.AJ.16.244; 11.AJ.16.243; 11.AJ.16.247;11.AJ.18.157; 11.AJ.18.158; 11.AJ.18.196; 11.AJ.18.223; 11.AJ.18.240;11.AJ.18.244; 11.AJ.18.243; 11.AJ.18.247; 11.AJ.26.157; 11.AJ.26.158;11.AJ.26.196; 11.AJ.26.223; 11.AJ.26.240; 11.AJ.26.244; 11.AJ.26.243;11.AJ.26.247; 11.AJ.27.157; 11.AJ.27.158; 11.AJ.27.196; 11.AJ.27.223;11.AJ.27.240; 11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247; 11.AJ.29.157;11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240; 11.AJ.29.244;11.AJ.29.243; 11.AJ.29.247; 11.AJ.54.157; 11.AJ.54.158; 11.AJ.54.196;11.AJ.54.223; 11.AJ.54.240; 11.AJ.54.244; 11.AJ.54.243; 11.AJ.54.247;11.AJ.55.157; 11.AJ.55.158; 11.AJ.55.196; 11.AJ.55.223; 11.AJ.55.240;11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157; 11.AJ.56.158;11.AJ.56.196; 11.AJ.56.223; 11.AJ.56.240; 11.AJ.56.244; 11.AJ.56.243;11.AJ.56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196;11.AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ.157.243;11.AJ.157.247; 11.AJ.196.157; 11.AJ.196.158; 11.AJ.196.196;11.AJ.196.223; 11.AJ.196.240; 11.AJ.196.244; 11.AJ.196.243;11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158; 11.AJ.223.196;11.AJ.223.223; 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243;11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ.240.196;11.AJ.240.223; 11.AJ.240.240; 11.AJ.240.244; 11.AJ.240.243;11.AJ.240.247; 11.AJ.244.157; 11.AJ.244.158; 11.AJ.244.196;11.AJ.244.223; 11.AJ.244.240; 11.AJ.244.244; 11.AJ.244.243;11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196;11.AJ.247.223; 11.AJ.247.240; 11.AJ.247.244; 11.AJ.247.243;11.AJ.247.247; Prodrugs of 11.AN 11.AN.4.157; 11.AN.4.158; 11.AN.4.196;11.AN.4.223; 11.AN.4.240; 11.AN.4.244; 11.AN.4.243; 11.AN.4.247;11.AN.5.157; 11.AN.5.158; 11.AN.5.196; 11.AN.5.223; 11.AN.5.240;11.AN.5.244; 11.AN.5.243; 11.AN.5.247; 11.AN.7.157; 11.AN.7.158;11.AN.7.196; 11.AN.7.223; 11.AN.7.240; 11.AN.7.244; 11.AN.7.243;11.AN.7.247; 11.AN.15.157; 11.AN.15.158; 11.AN.15.196; 11.AN.15.223;11.AN.15.240; 11.AN.15.244; 11.AN.15.243; 11.AN.15.247; 11.AN.16.157;11.AN.16.158; 11.AN.16.196; 11.AN.16.223; 11.AN.16.240; 11.AN.16.244;11.AN.16.243; 11.AN.16.247; 11.AN.18.157; 11.AN.18.158; 11.AN.18.196;11.AN.18.223; 11.AN.18.240; 11.AN.18.244; 11.AN.18.243; 11.AN.18.247;11.AN.26.157; 11.AN.26.158; 11.AN.26.196; 11.AN.26.223; 11.AN.26.240;11.AN.26.244; 11.AN.26.243; 11.AN.26.247; 11.AN.27.157; 11.AN.27.158;11.AN.27.196; 11.AN.27.223; 11.AN.27.240; 11.AN.27.244; 11.AN.27.243;11.AN.27.247; 11.AN.29.157; 11.AN.29.158; 11.AN.29.196; 11.AN.29.223;11.AN.29.240; 11.AN.29.244; 11.AN.29.243; 11.AN.29.247; 11.AN.54.157;11.AN.54.158; 11.AN.54.196; 11.AN.54.223; 11.AN.54.240; 11.AN.54.244;11.AN.54.243; 11.AN.54.247; 11.AN.55.157; 11.AN.55.158; 11.AN.55.196;11.AN.55.223; 11.AN.55.240; 11.AN.55.244; 11.AN.55.243; 11.AN.55.247;11.AN.56.157; 11.AN.56.158; 11.AN.56.196; 11.AN.56.223; 11.AN.56.240;11.AN.56.244; 11.AN.56.243; 11.AN.56.247; 11.AN.157.157; 11.AN.157.158;11.AN.157.196; 11.AN.157.223; 11.AN.157.240; 11.AN.157.244;11.AN.157.243; 11.AN.157.247; 11.AN.196.157; 11.AN.196.158;11.AN.196.196; 11.AN.196.223; 11.AN.196.240; 11.AN.196.244;11.AN.196.243; 11.AN.196.247; 11.AN.223.157; 11.AN.223.158;11.AN.223.196; 11.AN.223.223; 11.AN.223.240; 11.AN.223.244;11.AN.223.243; 11.AN.223.247; 11.AN.240.157; 11.AN.240.158;11.AN.240.196; 11.AN.240.223; 11.AN.240.240; 11.AN.240.244;11.AN.240.243; 11.AN.240.247; 11.AN.244.157; 11.AN.244.158;11.AN.244.196; 11.AN.244.223; 11.AN.244.240; 11.AN.244.244;11.AN.244.243; 11.AN.244.247; 11.AN.247.157; 11.AN.247.158;11.AN.247.196; 11.AN.247.223; 11.AN.247.240; 11.AN.247.244;11.AN.247.243; 11.AN.247.247; Prodrugs of 11.AP 11.AP.4.157;11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240; 11.AP.4.244;11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158; 11.AP.5.196;11.AP.5.223; 11.AP.5.240; 11.AP.5.244; 11.AP.5.243; 11.AP.5.247;11.AP.7.157; 11.AP.7.158; 11.AP.7.196; 11.AP.7.223; 11.AP.7.240;11.AP.7.244; 11.AP.7.243; 11.AP.7.247; 11.AP.15.157; 11.AP.15.158;11.AP.15.196; 11.AP.15.223; 11.AP.15.240; 11.AP.15.244; 11.AP.15.243;11.AP.15.247; 11.AP.16.157; 11.AP.16.158; 11.AP.16.196; 11.AP.16.223;11.AP.16.240; 11.AP.16.244; 11.AP.16.243; 11.AP.16.247; 11.AP.18.157;11.AP.18.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240; 11.AP.18.244;11.AP.18.243; 11.AP.18.247; 11.AP.26.157; 11.AP.26.158; 11.AP.26.196;11.AP.26.223; 11.AP.26.240; 11.AP.26.244; 11.AP.26.243; 11.AP.26.247;11.AP.27.157; 11.AP.27.158; 11.AP.27.196; 11.AP.27.223; 11.AP.27.240;11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157; 11.AP.29.158;11.AP.29.196; 11.AP.29.223; 11.AP.29.240; 11.AP.29.244; 11.AP.29.243;11.AP.29.247; 11.AP.54.157; 11.AP.54.158; 11.AP.54.196; 11.AP.54.223;11.AP.54.240; 11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157;11.AP.55.158; 11.AP.55.196; 11.AP.55.223; 11.AP.55.240; 11.AP.55.244;11.AP.55.243; 11.AP.55.247; 11.AP.56.157; 11.AP.56.158; 11.AP.56.196;11.AP.56.223; 11.AP.56.240; 11.AP.56.244; 11.AP.56.243; 11.AP.56.247;11.AP.157.157; 11.AP.157.158; 11.AP.157.196; 11.AP.157.223;11.AP.157.240; 11.AP.157.244; 11.AP.157.243; 11.AP.157.247;11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP.196.223;11.AP.196.240; 11.AP.196.244; 11.AP.196.243; 11.AP.196.247;11.AP.223.157; 11.AP.223.158; 11.AP.223.196; 11.AP.223.223;11.AP.223.240; 11.AP.223.244; 11.AP.223.243; 11.AP.223.247;11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223;11.AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247;11.AP.244.157; 11.AP.244.158; 11.AP.244.196; 11.AP.244.223;11.AP.244.240; 11.AP.244.244; 11.AP.244.243; 11.AP.244.247;11.AP.247.157; 11.AP.247.158; 11.AP.247.196; 11.AP.247.223;11.AP.247.240; 11.AP.247.244; 11.AP.247.243; 11.AP.247.247; Prodrugs of11.AZ 11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240;11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158;11.AZ.5.196; 11.AZ.5.223; 11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243;11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158; 11.AZ.7.196; 11.AZ.7.223;11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247; 11.AZ.15.157;11.AZ.15.158; 11.AZ.15.196; 11.AZ.15.223; 11.AZ.15.240; 11.AZ.15.244;11.AZ.15.243; 11.AZ.15.247; 11.AZ.16.157; 11.AZ.16.158; 11.AZ.16.196;11.AZ.16.223; 11.AZ.16.240; 11.AZ.16.244; 11.AZ.16.243; 11.AZ.16.247;11.AZ.18.157; 11.AZ.18.158; 11.AZ.18.196; 11.AZ.18.223; 11.AZ.18.240;11.AZ.18.244; 11.AZ.18.243; 11.AZ.18.247; 11.AZ.26.157; 11.AZ.26.158;11.AZ.26.196; 11.AZ.26.223; 11.AZ.26.240; 11.AZ.26.244; 11.AZ.26.243;11.AZ.26.247; 11.AZ.27.157; 11.AZ.27.158; 11.AZ.27.196; 11.AZ.27.223;11.AZ.27.240; 11.AZ.27.244; 11.AZ.27.243; 11.AZ.27.247; 11.AZ.29.157;11.AZ.29.158; 11.AZ.29.196; 11.AZ.29.223; 11.AZ.29.240; 11.AZ.29.244;11.AZ.29.243; 11.AZ.29.247; 11.AZ.54.157; 11.AZ.54.158; 11.AZ.54.196;11.AZ.54.223; 11.AZ.54.240; 11.AZ.54.244; 11.AZ.54.243; 11.AZ.54.247;11.AZ.55.157; 11.AZ.55.158; 11.AZ.55.196; 11.AZ.55.223; 11.AZ.55.240;11.AZ.55.244; 11.AZ.55.243; 11.AZ.55.247; 11.AZ.56.157; 11.AZ.56.158;11.AZ.56.196; 11.AZ.56.223; 11.AZ.56.240; 11.AZ.56.244; 11.AZ.56.243;11.AZ.56.247; 11.AZ.157.157; 11.AZ.157.158; 11.AZ.157.196;11.AZ.157.223; 11.AZ.157.240; 11.AZ.157.244; 11.AZ.157.243;11.AZ.157.247; 11.AZ.196.157; 11.AZ.196.158; 11.AZ.196.196;11.AZ.196.223; 11.AZ.196.240; 11.AZ.196.244; 11.AZ.196.243;11.AZ.196.247; 11.AZ.223.157; 11.AZ.223.158; 11.AZ.223.196;11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244; 11.AZ.223.243;11.AZ.223.247; 11.AZ.240.157; 11.AZ.240.158; 11.AZ.240.196;11.AZ.240.223; 11.AZ.240.240; 11.AZ.240.244; 11.AZ.240.243;11.AZ.240.247; 11.AZ.244.157; 11.AZ.244.158; 11.AZ.244.196;11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244; 11.AZ.244.243;11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158; 11.AZ.247.196;11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244; 11.AZ.247.243;11.AZ.247.247; Prodrugs of 11.BF 11.BF.4.157; 11.BF.4.158; 11.BF.4.196;11.BF.4.223; 11.BF.4.240; 11.BF.4.244; 11.BF.4.243; 11.BF.4.247;11.BF.5.157; 11.BF.5.158; 11.BF.5.196; 11.BF.5.223; 11.BF.5.240;11.BF.5.244; 11.BF.5.243; 11.BF.5.247; 11.BF.7.157; 11.BF.7.158;11.BF.7.196; 11.BF.7.223; 11.BF.7.240; 11.BF.7.244; 11.BF.7.243;11.BF.7.247; 11.BF.15.157; 11.BF.15.158; 11.BF.15.196; 11.BF.15.223;11.BF.15.240; 11.BF.15.244; 11.BF.15.243; 11.BF.15.247; 11.BF.16.157;11.BF.16.158; 11.BF.16.196; 11.BF.16.223; 11.BF.16.240; 11.BF.16.244;11.BF.16.243; 11.BF.16.247; 11.BF.18.157; 11.BF.18.158; 11.BF.18.196;11.BF.18.223; 11.BF.18.240; 11.BF.18.244; 11.BF.18.243; 11.BF.18.247;11.BF.26.157; 11.BF.26.158; 11.BF.26.196; 11.BF.26.223; 11.BF.26.240;11.BF.26.244; 11.BF.26.243; 11.BF.26.247; 11.BF.27.157; 11.BF.27.158;11.BF.27.196; 11.BF.27.223; 11.BF.27.240; 11.BF.27.244; 11.BF.27.243;11.BF.27.247; 11.BF.29.157; 11.BF.29.158; 11.BF.29.196; 11.BF.29.223;11.BF.29.240; 11.BF.29.244; 11.BF.29.243; 11.BF.29.247; 11.BF.54.157;11.BF.54.158; 11.BF.54.196; 11.BF.54.223; 11.BF.54.240; 11.BF.54.244;11.BF.54.243; 11.BF.54.247; 11.BF.55.157; 11.BF.55.158; 11.BF.55.196;11.BF.55.223; 11.BF.55.240; 11.BF.55.244; 11.BF.55.243; 11.BF.55.247;11.BF.56.157; 11.BF.56.158; 11.BF.56.196; 11.BF.56.223; 11.BF.56.240;11.BF.56.244; 11.BF.56.243; 11.BF.56.247; 11.BF.157.157; 11.BF.157.158;11.BF.157.196; 11.BF.157.223; 11.BF.157.240; 11.BF.157.244;11.BF.157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158;11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244;11.BF.196.243; 11.BF.196.247; 11.BF.223.157; 11.BF.223.158;11.BF.223.196; 11.BF.223.223; 11.BF.223.240; 11.BF.223.244;11.BF.223.243; 11.BF.223.247; 11.BF.240.157; 11.BF.240.158;11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244;11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158;11.BF.244.196; 11.BF.244.223; 11.BF.244.240; 11.BF.244.244;11.BF.244.243; 11.BF.244.247; 11.BF.247.157; 11.BF.247.158;11.BF.247.196; 11.BF.247.223; 11.BF.247.240; 11.BF.247.244;11.BF.247.243; 11.BF.247.247; Prodrugs of 11.CI 11.CI.4.157;11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244;11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196;11.CI.5.223; 11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247;11.CI.7.157; 11.CI.7.158; 11.CI.7.196; 11.CI.7.223; 11.CI.7.240;11.CI.7.244; 11.CI.7.243; 11.CI.7.247; 11.CI.15.157; 11.CI.15.158;11.CI.15.196; 11.CI.15.223; 11.CI.15.240; 11.CI.15.244; 11.CI.15.243;11.CI.15.247; 11.CI.16.157; 11.CI.16.158; 11.CI.16.196; 11.CI.16.223;11.CI.16.240; 11.CI.16.244; 11.CI.16.243; 11.CI.16.247; 11.CI.18.157;11.CI.18.158; 11.CI.18.196; 11.CI.18.223; 11.CI.18.240; 11.CI.18.244;11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158; 11.CI.26.196;11.CI.26.223; 11.CI.26.240; 11.CI.26.244; 11.CI.26.243; 11.CI.26.247;11.CI.27.157; 11.CI.27.158; 11.CI.27.196; 11.CI.27.223; 11.CI.27.240;11.CI.27.244; 11.CI.27.243; 11.CI.27.247; 11.CI.29.157; 11.CI.29.158;11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244; 11.CI.29.243;11.CI.29.247; 11.CI.54.157; 11.CI.54.158; 11.CI.54.196; 11.CI.54.223;11.CI.54.240; 11.CI.54.244; 11.CI.54.243; 11.CI.54.247; 11.CI.55.157;11.CI.55.158; 11.CI.55.196; 11.CI.55.223; 11.CI.55.240; 11.CI.55.244;11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158; 11.CI.56.196;11.CI.56.223; 11.CI.56.240; 11.CI.56.244; 11.CI.56.243; 11.CI.56.247;11.CI.157.157; 11.CI.157.158; 11.CI.157.196; 11.CI.157.223;11.CI.157.240; 11.CI.157.244; 11.CI.157.243; 11.CI.157.247;11.CI.196.157; 11.CI.196.158; 11.CI.196.196; 11.CI.196.223;11.CI.196.240; 11.CI.196.244; 11.CI.196.243; 11.CI.196.247;11.CI.223.157; 11.CI.223.158; 11.CI.223.196; 11.CI.223.223;11.CI.223.240; 11.CI.223.244; 11.CI.223.243; 11.CI.223.247;11.CI.240.157; 11.CI.240.158; 11.CI.240.196; 11.CI.240.223;11.CI.240.240; 11.CI.240.244; 11.CI.240.243; 11.CI.240.247;11.CI.244.157; 11.CI.244.158; 11.CI.244.196; 11.CI.244.223;11.CI.244.240; 11.CI.244.244; 11.CI.244.243; 11.CI.244.247;11.CI.247.157; 11.CI.247.158; 11.CI.247.196; 11.CI.247.223;11.CI.247.240; 11.CI.247.244; 11.CI.247.243; 11.CI.247.247; Prodrugs of11.CO 11.CO.4.157; 11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240;11.CO.4.244; 11.CO.4.243; 11.CO.4.247; 11.CO.5.157; 11.CO.5.158;11.CO.5.196; 11.CO.5.223; 11.CO.5.240; 11.CO.5.244; 11.CO.5.243;11.CO.5.247; 11.CO.7.157; 11.CO.7.158; 11.CO.7.196; 11.CO.7.223;11.CO.7.240; 11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157;11.CO.15.158; 11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244;11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158; 11.CO.16.196;11.CO.16.223; 11.CO.16.240; 11.CO.16.244; 11.CO.16.243; 11.CO.16.247;11.CO.18.157; 11.CO.18.158; 11.CO.18.196; 11.CO.18.223; 11.CO.18.240;11.CO.18.244; 11.CO.18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158;11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244; 11.CO.26.243;11.CO.26.247; 11.CO.27.157; 11.CO.27.158; 11.CO.27.196; 11.CO.27.223;11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157;11.CO.29.158; 11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244;11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 11.CO.54.196;11.CO.54.223; 11.CO.54.240; 11.CO.54.244; 11.CO.54.243; 11.CO.54.247;11.CO.55.157; 11.CO.55.158; 11.CO.55.196; 11.CO.55.223; 11.CO.55.240;11.CO.55.244; 11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158;11.CO.56.196; 11.CO.56.223; 11.CO.56.240; 11.CO.56.244; 11.CO.56.243;11.CO.56.247; 11.CO.157.157; 11.CO.157.158; 11.CO.157.196;11.CO.157.223; 11.CO.157.240; 11.CO.157.244; 11.CO.157.243;11.CO.157.247; 11.CO.196.157; 11.CO.196.158; 11.CO.196.196;11.CO.196.223; 11.CO.196.240; 11.CO.196.244; 11.CO.196.243;11.CO.196.247; 11.CO.223.157; 11.CO.223.158; 11.CO.223.196;11.CO.223.223; 11.CO.223.240; 11.CO.223.244; 11.CO.223.243;11.CO.223.247; 11.CO.240.157; 11.CO.240.158; 11.CO.240.196;11.CO.240.223; 11.CO.240.240; 11.CO.240.244; 11.CO.240.243;11.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196;11.CO.244.223; 11.CO.244.240; 11.CO.244.244; 11.CO.244.243;11.CO.244.247; 11.CO.247.157; 11.CO.247.158; 11.CO.247.196;11.CO.247.223; 11.CO.247.240; 11.CO.247.244; 11.CO.247.243;11.CO.247.247; Prodrugs of 12.AH 12.AH.4.157; 12.AH.4.158; 12.AH.4.196;12.AH.4.223; 12.AH.4.240; 12.AH.4.244; 12.AH.4.243; 12.AH.4.247;12.AH.5.157; 12.AH.5.158; 12.AH.5.196; 12.AH.5.223; 12.AH.5.240;12.AH.5.244; 12.AH.5.243; 12.AH.5.247; 12.AH.7.157; 12.AH.7.158;12.AH.7.196; 12.AH.7.223; 12.AH.7.240; 12.AH.7.244; 12.AH.7.243;12.AH.7.247; 12.AH.15.157; 12.AH.15.158; 12.AH.15.196; 12.AH.15.223;12.AH.15.240; 12.AH.15.244; 12.AH.15.243; 12.AH.15.247; 12.AH.16.157;12.AH.16.158; 12.AH.16.196; 12.AH.16.223; 12.AH.16.240; 12.AH.16.244;12.AH.16.243; 12.AH.16.247; 12.AH.18.157; 12.AH.18.158; 12.AH.18.196;12.AH.18.223; 12.AH.18.240; 12.AH.18.244; 12.AH.18.243; 12.AH.18.247;12.AH.26.157; 12.AH.26.158; 12.AH.26.196; 12.AH.26.223; 12.AH.26.240;12.AH.26.244; 12.AH.26.243; 12.AH.26.247; 12.AH.27.157; 12.AH.27.158;12.AH.27.196; 12.AH.27.223; 12.AH.27.240; 12.AH.27.244; 12.AH.27.243;12.AH.27.247; 12.AH.29.157; 12.AH.29.158; 12.AH.29.196; 12.AH.29.223;12.AH.29.240; 12.AH.29.244; 12.AH.29.243; 12.AH.29.247; 12.AH.54.157;12.AH.54.158; 12.AH.54.196; 12.AH.54.223; 12.AH.54.240; 12.AH.54.244;12.AH.54.243; 12.AH.54.247; 12.AH.55.157; 12.AH.55.158; 12.AH.55.196;12.AH.55.223; 12.AH.55.240; 12.AH.55.244; 12.AH.55.243; 12.AH.55.247;12.AH.56.157; 12.AH.56.158; 12.AH.56.196; 12.AH.56.223; 12.AH.56.240;12.AH.56.244; 12.AH.56.243; 12.AH.56.247; 12.AH.157.157; 12.AH.157.158;12.AH.157.196; 12.AH.157.223; 12.AH.157.240; 12.AH.157.244;12.AH.157.243; 12.AH.157.247; 12.AH.196.157; 12.AH.196.158;12.AH.196.196; 12.AH.196.223; 12.AH.196.240; 12.AH.196.244;12.AH.196.243; 12.AH.196.247; 12.AH.223.157; 12.AH.223.158;12.AH.223.196; 12.AH.223.223; 12.AH.223.240; 12.AH.223.244;12.AH.223.243; 12.AH.223.247; 12.AH.240.157; 12.AH.240.158;12.AH.240.196; 12.AH.240.223; 12.AH.240.240; 12.AH.240.244;12.AH.240.243; 12.AH.240.247; 12.AH.244.157; 12.AH.244.158;12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244;12.AH.244.243; 12.AH.244.247; 12.AH.247.157; 12.AH.247.158;12.AH.247.196; 12.AH.247.223; 12.AH.247.240; 12.AH.247.244;12.AH.247.243; 12.AH.247.247; Prodrugs of 12.AJ 12.AJ.4.157;12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244;12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196;12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247;12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240;12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ.15.157; 12.AJ.15.158;12.AJ.15.196; 12.AJ.15.223; 12.AJ.15.240; 12.AJ.15.244; 12.AJ.15.243;12.AJ.15.247; 12.AJ.16.157; 12.AJ.16.158; 12.AJ.16.196; 12.AJ.16.223;12.AJ.16.240; 12.AJ.16.244; 12.AJ.16.243; 12.AJ.16.247; 12.AJ.18.157;12.AJ.18.158; 12.AJ.18.196; 12.AJ.18.223; 12.AJ.18.240; 12.AJ.18.244;12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157; 12.AJ.26.158; 12.AJ.26.196;12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244; 12.AJ.26.243; 12.AJ.26.247;12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240;12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158;12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244; 12.AJ.29.243;12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158; 12.AJ.54.196; 12.AJ.54.223;12.AJ.54.240; 12.AJ.54.244; 12.AJ.54.243; 12.AJ.54.247; 12.AJ.55.157;12.AJ.55.158; 12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240; 12.AJ.55.244;12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158; 12.AJ.56.196;12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244; 12.AJ.56.243; 12.AJ.56.247;12.AJ.157.157; 12.AJ.157.158; 12.AJ.157.196; 12.AJ.157.223;12.AJ.157.240; 12.AJ.157.244; 12.AJ.157.243; 12.AJ.157.247;12.AJ.196.157; 12.AJ.196.158; 12.AJ.196.196; 12.AJ.196.223;12.AJ.196.240; 12.AJ.196.244; 12.AJ.196.243; 12.AJ.196.247;12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196; 12.AJ.223.223;12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247;12.AJ.240.157; 12.AJ.240.158; 12.AJ.240.196; 12.AJ.240.223;12.AJ.240.240; 12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247;12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196; 12.AJ.244.223;12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247;12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223;12.AJ.247.240; 12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247; Prodrugs of12.AN 12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240;12.AN.4.244; 12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158;12.AN.5.196; 12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243;12.AN.5.247; 12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223;12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157;12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244;12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158; 12.AN.16.196;12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12.AN.16.243; 12.AN.16.247;12.AN.18.157; 12.AN.18.158; 12.AN.18.196; 12.AN.18.223; 12.AN.18.240;12.AN.18.244; 12.AN.18.243; 12.AN.18.247; 12.AN.26.157; 12.AN.26.158;12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244; 12.AN.26.243;12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196; 12.AN.27.223;12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247; 12.AN.29.157;12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244;12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158; 12.AN.54.196;12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247;12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223; 12.AN.55.240;12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158;12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243;12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196;12.AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243;12.AN.157.247; 12.AN.196.157; 12.AN.196.158; 12.AN.196.196;12.AN.196.223; 12.AN.196.240; 12.AN.196.244; 12.AN.196.243;12.AN.196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196;12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243;12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196;12.AN.240.223; 12.AN.240.240; 12.AN.240.244; 12.AN.240.243;12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196;12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243;12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196;12.AN.247.223; 12.AN.247.240; 12.AN.247.244; 12.AN.247.243;12.AN.247.247; Prodrugs of 12.AP 12.AP.4.157; 12.AP.4.158; 12.AP.4.196;12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247;12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240;12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158;12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243;12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223;12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157;12.AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244;12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158; 12.AP.18.196;12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247;12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240;12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158;12.AP.27.196; 12.AP.27.223; 12.AP.27.240; 12.AP.27.244; 12.AP.27.243;12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP.29.196; 12.AP.29.223;12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157;12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240; 12.AP.54.244;12.AP.54.243; 12.AP.54.247; 12.AP.55.157; 12.AP.55.158; 12.AP.55.196;12.AP.55.223; 12.AP.55.240; 12.AP.55.244; 12.AP.55.243; 12.AP.55.247;12.AP.56.157; 12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240;12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP.157.157; 12.AP.157.158;12.AP.157.196; 12.AP.157.223; 12.AP.157.240; 12.AP.157.244;12.AP.157.243; 12.AP.157.247; 12.AP.196.157; 12.AP.196.158;12.AP.196.196; 12.AP.196.223; 12.AP.196.240; 12.AP.196.244;12.AP.196.243; 12.AP.196.247; 12.AP.223.157; 12.AP.223.158;12.AP.223.196; 12.AP.223.223; 12.AP.223.240; 12.AP.223.244;12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158;12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244;12.AP.240.243; 12.AP.240.247; 12.AP.244.157; 12.AP.244.158;12.AP.244.196; 12.AP.244.223; 12.AP.244.240; 12.AP.244.244;12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158;12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244;12.AP.247.243; 12.AP.247.247; Prodrugs of 12.AZ 12.AZ.4.157;12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244;12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158; 12.AZ.5.196;12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247;12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240;12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157; 12.AZ.15.158;12.AZ.15.196; 12.AZ.15.223; 12.AZ.15.240; 12.AZ.15.244; 12.AZ.15.243;12.AZ.15.247; 12.AZ.16.157; 12.AZ.16.158; 12.AZ.16.196; 12.AZ.16.223;12.AZ.16.240; 12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157;12.AZ.18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240; 12.AZ.18.244;12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157; 12.AZ.26.158; 12.AZ.26.196;12.AZ.26.223; 12.AZ.26.240; 12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247;12.AZ.27.157; 12.AZ.27.158; 12.AZ.27.196; 12.AZ.27.223; 12.AZ.27.240;12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157; 12.AZ.29.158;12.AZ.29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243;12.AZ.29.247; 12.AZ.54.157; 12.AZ.54.158; 12.AZ.54.196; 12.AZ.54.223;12.AZ.54.240; 12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157;12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244;12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157; 12.AZ.56.158; 12.AZ.56.196;12.AZ.56.223; 12.AZ.56.240; 12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247;12.AZ.157.157; 12.AZ.157.158; 12.AZ.157.196; 12.AZ.157.223;12.AZ.157.240; 12.AZ.157.244; 12.AZ.157.243; 12.AZ.157.247;12.AZ.196.157; 12.AZ.196.158; 12.AZ.196.196; 12.AZ.196.223;12.AZ.196.240; 12.AZ.196.244; 12.AZ.196.243; 12.AZ.196.247;12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223;12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247;12.AZ.240.157; 12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223;12.AZ.240.240; 12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247;12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223;12.AZ.244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247;12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223;12.AZ.247.240; 12.AZ.247.244; 12.AZ.247.243; 12.AZ.247.247; Prodrugs of12.BF 12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240;12.BF.4.244; 12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158;12.BF.5.196; 12.BF.5.223; 12.BF.5.240; 12.BF.5.244; 12.BF.5.243;12.BF.5.247; 12.BF.7.157; 12.BF.7.158; 12.BF.7.196; 12.BF.7.223;12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247; 12.BF.15.157;12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240; 12.BF.15.244;12.BF.15.243; 12.BF.15.247; 12.BF.16.157; 12.BF.16.158; 12.BF.16.196;12.BF.16.223; 12.BF.16.240; 12.BF.16.244; 12.BF.16.243; 12.BF.16.247;12.BF.18.157; 12.BF.18.158; 12.BF.18.196; 12.BF.18.223; 12.BF.18.240;12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157; 12.BF.26.158;12.BF.26.196; 12.BF.26.223; 12.BF.26.240; 12.BF.26.244; 12.BF.26.243;12.BF.26.247; 12.BF.27.157; 12.BF.27.158; 12.BF.27.196; 12.BF.27.223;12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12.BF.29.157;12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240; 12.BF.29.244;12.BF.29.243; 12.BF.29.247; 12.BF.54.157; 12.BF.54.158; 12.BF.54.196;12.BF.54.223; 12.BF.54.240; 12.BF.54.244; 12.BF.54.243; 12.BF.54.247;12.BF.55.157; 12.BF.55.158; 12.BF.55.196; 12.BF.55.223; 12.BF.55.240;12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157; 12.BF.56.158;12.BF.56.196; 12.BF.56.223; 12.BF.56.240; 12.BF.56.244; 12.BF.56.243;12.BF.56.247; 12.BF.157.157; 12.BF.157.158; 12.BF.157.196;12.BF.157.223; 12.BF.157.240; 12.BF.157.244; 12.BF.157.243;12.BF.157.247; 12.BF.196.157; 12.BF.196.158; 12.BF.196.196;12.BF.196.223; 12.BF.196.240; 12.BF.196.244; 12.BF.196.243;12.BF.196.247; 12.BF.223.157; 12.BF.223.158; 12.BF.223.196;12.BF.223.223; 12.BF.223.240; 12.BF.223.244; 12.BF.223.243;12.BF.223.247; 12.BF.240.157; 12.BF.240.158; 12.BF.240.196;12.BF.240.223; 12.BF.240.240; 12.BF.240.244; 12.BF.240.243;12.BF.240.247; 12.BF.244.157; 12.BF.244.158; 12.BF.244.196;12.BF.244.223; 12.BF.244.240; 12.BF.244.244; 12.BF.244.243;12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12.BF.247.196;12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12.BF.247.243;12.BF.247.247; Prodrugs of 12.CI 12.CI.4.157; 12.CI.4.158; 12.CI.4.196;12.CI.4.223; 12.CI.4.240; 12.CI.4.244; 12.CI.4.243; 12.CI.4.247;12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223; 12.CI.5.240;12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158;12.CI.7.196; 12.CI.7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243;12.CI.7.247; 12.CI.15.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223;12.CI.15.240; 12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157;12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CI.16.244;12.CI.16.243; 12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196;12.CI.18.223; 12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247;12.CI.26.157; 12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240;12.CI.26.244; 12.CI.26.243; 12.CI.26.247; 12.CI.27.157; 12.CI.27.158;12.CI.27.196; 12.CI.27.223; 12.CI.27.240; 12.CI.27.244; 12.CI.27.243;12.CI.27.247; 12.CI.29.157; 12.CI.29.158; 12.CI.29.196; 12.CI.29.223;12.CI.29.240; 12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157;12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240; 12.CI.54.244;12.CI.54.243; 12.CI.54.247; 12.CI.55.157; 12.CI.55.158; 12.CI.55.196;12.CI.55.223; 12.CI.55.240; 12.CI.55.244; 12.CI.55.243; 12.CI.55.247;12.CI.56.157; 12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240;12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157; 12.CI.157.158;12.CI.157.196; 12.CI.157.223; 12.CI.157.240; 12.CI.157.244;12.CI.157.243; 12.CI.157.247; 12.CI.196.157; 12.CI.196.158;12.CI.196.196; 12.CI.196.223; 12.CI.196.240; 12.CI.196.244;12.CI.196.243; 12.CI.196.247; 12.CI.223.157; 12.CI.223.158;12.CI.223.196; 12.CI.223.223; 12.CI.223.240; 12.CI.223.244;12.CI.223.243; 12.CI.223.247; 12.CI.240.157; 12.CI.240.158;12.CI.240.196; 12.CI.240.223; 12.CI.240.240; 12.CI.240.244;12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158;12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244;12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158;12.CI.247.196; 12.CI.247.223; 12.CI.247.240; 12.CI.247.244;12.CI.247.243; 12.CI.247.247; Prodrugs of 12.CO 12.CO.4.157;12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244;12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196;12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.CO.5.243; 12.CO.5.247;12.CO.7.157; 12.CO.7.158; 12.CO.7.196; 12.CO.7.223; 12.CO.7.240;12.CO.7.244; 12.CO.7.243; 12.CO.7.247; 12.CO.15.157; 12.CO.15.158;12.CO.15.196; 12.CO.15.223; 12.CO.15.240; 12.CO.15.244; 12.CO.15.243;12.CO.15.247; 12.CO.16.157; 12.CO.16.158; 12.CO.16.196; 12.CO.16.223;12.CO.16.240; 12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157;12.CO.18.158; 12.CO.18.196; 12.CO.18.223; 12.CO.18.240; 12.CO.18.244;12.CO.18.243; 12.CO.18.247; 12.CO.26.157; 12.CO.26.158; 12.CO.26.196;12.CO.26.223; 12.CO.26.240; 12.CO.26.244; 12.CO.26.243; 12.CO.26.247;12.CO.27.157; 12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240;12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157; 12.CO.29.158;12.CO.29.196; 12.CO.29.223; 12.CO.29.240; 12.CO.29.244; 12.CO.29.243;12.CO.29.247; 12.CO.54.157; 12.CO.54.158; 12.CO.54.196; 12.CO.54.223;12.CO.54.240; 12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157;12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240; 12.CO.55.244;12.CO.55.243; 12.CO.55.247; 12.CO.56.157; 12.CO.56.158; 12.CO.56.196;12.CO.56.223; 12.CO.56.240; 12.CO.56.244; 12.CO.56.243; 12.CO.56.247;12.CO.157.157; 12.CO.157.158; 12.CO.157.196; 12.CO.157.223;12.CO.157.240; 12.CO.157.244; 12.CO.157.243; 12.CO.157.247;12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO.196.223;12.CO.196.240; 12.CO.196.244; 12.CO.196.243; 12.CO.196.247;12.CO.223.157; 12.CO.223.158; 12.CO.223.196; 12.CO.223.223;12.CO.223.240; 12.CO.223.244; 12.CO.223.243; 12.CO.223.247;12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223;12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247;12.CO.244.157; 12.CO.244.158; 12.CO.244.196; 12.CO.244.223;12.CO.244.240; 12.CO.244.244; 12.CO.244.243; 12.CO.244.247;12.CO.247.157; 12.CO.247.158; 12.CO.247.196; 12.CO.247.223;12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247. Prodrugs of13.B 13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231;13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154;13.B.228.157; 13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175;13.B.228.240; 13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230;13.B.229.231; 13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239;13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172;13.B.229.175; 13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229;13.B.230.230; 13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238;13.B.230.239; 13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169;13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228;13.B.231.229; 13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237;13.B.231.238; 13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166;13.B.231.169; 13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244;13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236;13.B.236.237; 13.B.236.238; 13.B.236.239; 13.B.236.154; 13.B.236.157;13.B.236.166; 13.B.236.169; 13.B.236.172; 13.B.236.175; 13.B.236.240;13.B.236.244; 13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231;13.B.237.236; 13.B.237.237; 13.B.237.238; 13.B.237.239; 13.B.237.154;13.B.237.157; 13.B.237.166; 13.B.237.169; 13.B.237.172; 13.B.237.175;13.B.237.240; 13.B.237.244; 13.B.238.228; 13.B.238.229; 13.B.238.230;13.B.238.231; 13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239;13.B.238.154; 13.B.238.157; 13.B.238.166; 13.B.238.169; 13.B.238.172;13.B.238.175; 13.B.238.240; 13.B.238.244; 13.B.239.228; 13.B.239.229;13.B.239.230; 13.B.239.231; 13.B.239.236; 13.B.239.237; 13.B.239.238;13.B.239.239; 13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169;13.B.239.172; 13.B.239.175; 13.B.239.240; 13.B.239.244; 13.B.154.228;13.B.154.229; 13.B.154.230; 13.B.154.231; 13.B.154.236; 13.B.154.237;13.B.154.238; 13.B.154.239; 13.B.154.154; 13.B.154.157; 13.B.154.166;13.B.154.169; 13.B.154.172; 13.B.154.175; 13.B.154.240; 13.B.154.244;13.B.157.228; 13.B.157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236;13.B.157.237; 13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157;13.B.157.166; 13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240;13.B.157.244; 13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231;13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154;13.B.166.157; 13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175;13.B.166.240; 13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230;13.B.169.231; 13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239;13.B.169.154; 13.B.169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172;13.B.169.175; 13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229;13.B.172.230; 13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238;13.B.172.239; 13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169;13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228;13.B.175.229; 13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237;13.B.175.238; 13.B.175.239; 13.B.175.154; 13.B.175.157; 13.B.175.166;13.B.175.169; 13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244;13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231; 13.B.240.236;13.B.240.237; 13.B.240.238; 13.B.240.239; 13.B.240.154; 13.B.240.157;13.B.240.166; 13.B.240.169; 13.B.240.172; 13.B.240.175; 13.B.240.240;13.B.240.244; 13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231;13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239; 13.B.244.154;13.B.244.157; 13.B.244.166; 13.B.244.169; 13.B.244.172; 13.B.244.175;13.B.244.240; 13.B.244.244; Prodrugs of 13.D 13.D.228.228; 13.D.228.229;13.D.228.230; 13.D.228.231; 13.D.228.236; 13.D.228.237; 13.D.228.238;13.D.228.239; 13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169;13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244; 13.D.229.228;13.D.229.229; 13.D.229.230; 13.D.229.231; 13.D.229.236; 13.D.229.237;13.D.229.238; 13.D.229.239; 13.D.229.154; 13.D.229.157; 13.D.229.166;13.D.229.169; 13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244;13.D.230.228; 13.D.230.229; 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13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;Prodrugs of 13.W 13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231;13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.228.154;13.W.228.157; 13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175;13.W.228.240; 13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230;13.W.229.231; 13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239;13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172;13.W.229.175; 13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229;13.W.230.230; 13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238;13.W.230.239; 13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169;13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228;13.W.231.229; 13.W.231.230; 13.W.231.231; 13.W.231.236; 13.W.231.237;13.W.231.238; 13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166;13.W.231.169; 13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244;13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W.236.231; 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13.W.154.175; 13.W.154.240; 13.W.154.244;13.W.157.228; 13.W.157.229; 13.W.157.230; 13.W.157.231; 13.W.157.236;13.W.157.237; 13.W.157.238; 13.W.157.239; 13.W.157.154; 13.W.157.157;13.W.157.166; 13.W.157.169; 13.W.157.172; 13.W.157.175; 13.W.157.240;13.W.157.244; 13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231;13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239; 13.W.166.154;13.W.166.157; 13.W.166.166; 13.W.166.169; 13.W.166.172; 13.W.166.175;13.W.166.240; 13.W.166.244; 13.W.169.228; 13.W.169.229; 13.W.169.230;13.W.169.231; 13.W.169.236; 13.W.169.237; 13.W.169.238; 13.W.169.239;13.W.169.154; 13.W.169.157; 13.W.169.166; 13.W.169.169; 13.W.169.172;13.W.169.175; 13.W.169.240; 13.W.169.244; 13.W.172.228; 13.W.172.229;13.W.172.230; 13.W.172.231; 13.W.172.236; 13.W.172.237; 13.W.172.238;13.W.172.239; 13.W.172.154; 13.W.172.157; 13.W.172.166; 13.W.172.169;13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244; 13.W.175.228;13.W.175.229; 13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237;13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157; 13.W.175.166;13.W.175.169; 13.W.175.172; 13.W.175.175; 13.W.175.240; 13.W.175.244;13.W.240.228; 13.W.240.229; 13.W.240.230; 13.W.240.231; 13.W.240.236;13.W.240.237; 13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157;13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175; 13.W.240.240;13.W.240.244; 13.W.244.228; 13.W.244.229; 13.W.244.230; 13.W.244.231;13.W.244.236; 13.W.244.237; 13.W.244.238; 13.W.244.239; 13.W.244.154;13.W.244.157; 13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175;13.W.244.240; 13.W.244.244; Prodrugs of 13.Y 13.Y.228.228; 13.Y.228.229;13.Y.228.230; 13.Y.228.231; 13.Y.228.236; 13.Y.228.237; 13.Y.228.238;13.Y.228.239; 13.Y.228.154; 13.Y.228.157; 13.Y.228.166; 13.Y.228.169;13.Y.228.172; 13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228;13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236; 13.Y.229.237;13.Y.229.238; 13.Y.229.239; 13.Y.229.154; 13.Y.229.157; 13.Y.229.166;13.Y.229.169; 13.Y.229.172; 13.Y.229.175; 13.Y.229.240; 13.Y.229.244;13.Y.230.228; 13.Y.230.229; 13.Y.230.230; 13.Y.230.231; 13.Y.230.236;13.Y.230.237; 13.Y.230.238; 13.Y.230.239; 13.Y.230.154; 13.Y.230.157;13.Y.230.166; 13.Y.230.169; 13.Y.230.172; 13.Y.230.175; 13.Y.230.240;13.Y.230.244; 13.Y.231.228; 13.Y.231.229; 13.Y.231.230; 13.Y.231.231;13.Y.231.236; 13.Y.231.237; 13.Y.231.238; 13.Y.231.239; 13.Y.231.154;13.Y.231.157; 13.Y.231.166; 13.Y.231.169; 13.Y.231.172; 13.Y.231.175;13.Y.231.240; 13.Y.231.244; 13.Y.236.228; 13.Y.236.229; 13.Y.236.230;13.Y.236.231; 13.Y.236.236; 13.Y.236.237; 13.Y.236.238; 13.Y.236.239;13.Y.236.154; 13.Y.236.157; 13.Y.236.166; 13.Y.236.169; 13.Y.236.172;13.Y.236.175; 13.Y.236.240; 13.Y.236.244; 13.Y.237.228; 13.Y.237.229;13.Y.237.230; 13.Y.237.231; 13.Y.237.236; 13.Y.237.237; 13.Y.237.238;13.Y.237.239; 13.Y.237.154; 13.Y.237.157; 13.Y.237.166; 13.Y.237.169;13.Y.237.172; 13.Y.237.175; 13.Y.237.240; 13.Y.237.244; 13.Y.238.228;13.Y.238.229; 13.Y.238.230; 13.Y.238.231; 13.Y.238.236; 13.Y.238.237;13.Y.238.238; 13.Y.238.239; 13.Y.238.154; 13.Y.238.157; 13.Y.238.166;13.Y.238.169; 13.Y.238.172; 13.Y.238.175; 13.Y.238.240; 13.Y.238.244;13.Y.239.228; 13.Y.239.229; 13.Y.239.230; 13.Y.239.231; 13.Y.239.236;13.Y.239.237; 13.Y.239.238; 13.Y.239.239; 13.Y.239.154; 13.Y.239.157;13.Y.239.166; 13.Y.239.169; 13.Y.239.172; 13.Y.239.175; 13.Y.239.240;13.Y.239.244; 13.Y.154.228; 13.Y.154.229; 13.Y.154.230; 13.Y.154.231;13.Y.154.236; 13.Y.154.237; 13.Y.154.238; 13.Y.154.239; 13.Y.154.154;13.Y.154.157; 13.Y.154.166; 13.Y.154.169; 13.Y.154.172; 13.Y.154.175;13.Y.154.240; 13.Y.154.244; 13.Y.157.228; 13.Y.157.229; 13.Y.157.230;13.Y.157.231; 13.Y.157.236; 13.Y.157.237; 13.Y.157.238; 13.Y.157.239;13.Y.157.154; 13.Y.157.157; 13.Y.157.166; 13.Y.157.169; 13.Y.157.172;13.Y.157.175; 13.Y.157.240; 13.Y.157.244; 13.Y.166.228; 13.Y.166.229;13.Y.166.230; 13.Y.166.231; 13.Y.166.236; 13.Y.166.237; 13.Y.166.238;13.Y.166.239; 13.Y.166.154; 13.Y.166.157; 13.Y.166.166; 13.Y.166.169;13.Y.166.172; 13.Y.166.175; 13.Y.166.240; 13.Y.166.244; 13.Y.169.228;13.Y.169.229; 13.Y.169.230; 13.Y.169.231; 13.Y.169.236; 13.Y.169.237;13.Y.169.238; 13.Y.169.239; 13.Y.169.154; 13.Y.169.157; 13.Y.169.166;13.Y.169.169; 13.Y.169.172; 13.Y.169.175; 13.Y.169.240; 13.Y.169.244;13.Y.172.228; 13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236;13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157;13.Y.172.166; 13.Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240;13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y.175.231;13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154;13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175;13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230;13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239;13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172;13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229;13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238;13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169;13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244; Prodrugs of14.AH 14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240;14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158;14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243;14.AH.5.247; 14.AH.7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223;14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157;14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240; 14.AH.15.244;14.AH.15.243; 14.AH.15.247; 14.AH.16.157; 14.AH.16.158; 14.AH.16.196;14.AH.16.223; 14.AH.16.240; 14.AH.16.244; 14.AH.16.243; 14.AH.16.247;14.AH.18.157; 14.AH.18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240;14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157; 14.AH.26.158;14.AH.26.196; 14.AH.26.223; 14.AH.26.240; 14.AH.26.244; 14.AH.26.243;14.AH.26.247; 14.AH.27.157; 14.AH.27.158; 14.AH.27.196; 14.AH.27.223;14.AH.27.240; 14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157;14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244;14.AH.29.243; 14.AH.29.247; 14.AH.54.157; 14.AH.54.158; 14.AH.54.196;14.AH.54.223; 14.AH.54.240; 14.AH.54.244; 14.AH.54.243; 14.AH.54.247;14.AH.55.157; 14.AH.55.158; 14.AH.55.196; 14.AH.55.223; 14.AH.55.240;14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157; 14.AH.56.158;14.AH.56.196; 14.AH.56.223; 14.AH.56.240; 14.AH.56.244; 14.AH.56.243;14.AH.56.247; 14.AH.157.157; 14.AH.157.158; 14.AH.157.196;14.AH.157.223; 14.AH.157.240; 14.AH.157.244; 14.AH.157.243;14.AH.157.247; 14.AH.196.157; 14.AH.196.158; 14.AH.196.196;14.AH.196.223; 14.AH.196.240; 14.AH.196.244; 14.AH.196.243;14.AH.196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196;14.AH.223.223; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243;14.AH.223.247; 14.AH.240.157; 14.AH.240.158; 14.AH.240.196;14.AH.240.223; 14.AH.240.240; 14.AH.240.244; 14.AH.240.243;14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196;14.AH.244.223; 14.AH.244.240; 14.AH.244.244; 14.AH.244.243;14.AH.244.247; 14.AH.247.157; 14.AH.247.158; 14.AH.247.196;14.AH.247.223; 14.AH.247.240; 14.AH.247.244; 14.AH.247.243;14.AH.247.247; Prodrugs of 14.AJ 14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196;14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247;14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240;14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158;14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243;14.AJ.7.247; 14.AJ.15.157; 14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223;14.AJ.15.240; 14.AJ.15.244; 14.AJ.15.243; 14.AJ.15.247; 14.AJ.16.157;14.AJ.16.158; 14.AJ.16.196; 14.AJ.16.223; 14.AJ.16.240; 14.AJ.16.244;14.AJ.16.243; 14.AJ.16.247; 14.AJ.18.157; 14.AJ.18.158; 14.AJ.18.196;14.AJ.18.223; 14.AJ.18.240; 14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247;14.AJ.26.157; 14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240;14.AJ.26.244; 14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157; 14.AJ.27.158;14.AJ.27.196; 14.AJ.27.223; 14.AJ.27.240; 14.AJ.27.244; 14.AJ.27.243;14.AJ.27.247; 14.AJ.29.157; 14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223;14.AJ.29.240; 14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157;14.AJ.54.158; 14.AJ.54.196; 14.AJ.54.223; 14.AJ.54.240; 14.AJ.54.244;14.AJ.54.243; 14.AJ.54.247; 14.AJ.55.157; 14.AJ.55.158; 14.AJ.55.196;14.AJ.55.223; 14.AJ.55.240; 14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247;14.AJ.56.157; 14.AJ.56.158; 14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240;14.AJ.56.244; 14.AJ.56.243; 14.AJ.56.247; 14.AJ.157.157; 14.AJ.157.158;14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240; 14.AJ.157.244;14.AJ.157.243; 14.AJ.157.247; 14.AJ.196.157; 14.AJ.196.158;14.AJ.196.196; 14.AJ.196.223; 14.AJ.196.240; 14.AJ.196.244;14.AJ.196.243; 14.AJ.196.247; 14.AJ.223.157; 14.AJ.223.158;14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240; 14.AJ.223.244;14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157; 14.AJ.240.158;14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240; 14.AJ.240.244;14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157; 14.AJ.244.158;14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244;14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157; 14.AJ.247.158;14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240; 14.AJ.247.244;14.AJ.247.243; 14.AJ.247.247; Prodrugs of 14.AN 14.AN.4.157;14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244;14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196;14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247;14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223; 14.AN.7.240;14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157; 14.AN.15.158;14.AN.15.196; 14.AN.15.223; 14.AN.15.240; 14.AN.15.244; 14.AN.15.243;14.AN.15.247; 14.AN.16.157; 14.AN.16.158; 14.AN.16.196; 14.AN.16.223;14.AN.16.240; 14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157;14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244;14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196;14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247;14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240;14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158;14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243;14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196; 14.AN.54.223;14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157;14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240; 14.AN.55.244;14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158; 14.AN.56.196;14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247;14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223;14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247;14.AN.196.157; 14.AN.196.158; 14.AN.196.196; 14.AN.196.223;14.AN.196.240; 14.AN.196.244; 14.AN.196.243; 14.AN.196.247;14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN.223.223;14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247;14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223;14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247;14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223;14.AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247;14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223;14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247; Prodrugs of14.AP 14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240;14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158;14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243;14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223;14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157;14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244;14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14.AP.16.158; 14.AP.16.196;14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247;14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240;14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158;14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243;14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223;14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157;14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244;14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196;14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247;14.AP.55.157; 14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240;14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158;14.AP.56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243;14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196;14.AP.157.223; 14.AP.157.240; 14.AP.157.244; 14.AP.157.243;14.AP.157.247; 14.AP.196.157; 14.AP.196.158; 14.AP.196.196;14.AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243;14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196;14.AP.223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243;14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196;14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243;14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196;14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243;14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196;14.AP.247.223; 14.AP.247.240; 14.AP.247.244; 14.AP.247.243;14.AP.247.247; Prodrugs of 14.AZ 14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196;14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247;14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240;14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158;14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243;14.AZ.7.247; 14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223;14.AZ.15.240; 14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157;14.AZ.16.158; 14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240; 14.AZ.16.244;14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157; 14.AZ.18.158; 14.AZ.18.196;14.AZ.18.223; 14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247;14.AZ.26.157; 14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240;14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158;14.AZ.27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243;14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223;14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157;14.AZ.54.158; 14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244;14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196;14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247;14.AZ.56.157; 14.AZ.56.158; 14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240;14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158;14.AZ.157.196; 14.AZ.157.223; 14.AZ.157.240; 14.AZ.157.244;14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157; 14.AZ.196.158;14.AZ.196.196; 14.AZ.196.223; 14.AZ.196.240; 14.AZ.196.244;14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157; 14.AZ.223.158;14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244;14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157; 14.AZ.240.158;14.AZ.240.196; 14.AZ.240.223; 14.AZ.240.240; 14.AZ.240.244;14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158;14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244;14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158;14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240; 14.AZ.247.244;14.AZ.247.243; 14.AZ.247.247; Prodrugs of 14.BF 14.BF.4.157;14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240; 14.BF.4.244;14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196;14.BF.5.223; 14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247;14.BF.7.157; 14.BF.7.158; 14.BF.7.196; 14.BF.7.223; 14.BF.7.240;14.BF.7.244; 14.BF.7.243; 14.BF.7.247; 14.BF.15.157; 14.BF.15.158;14.BF.15.196; 14.BF.15.223; 14.BF.15.240; 14.BF.15.244; 14.BF.15.243;14.BF.15.247; 14.BF.16.157; 14.BF.16.158; 14.BF.16.196; 14.BF.16.223;14.BF.16.240; 14.BF.16.244; 14.BF.16.243; 14.BF.16.247; 14.BF.18.157;14.BF.18.158; 14.BF.18.196; 14.BF.18.223; 14.BF.18.240; 14.BF.18.244;14.BF.18.243; 14.BF.18.247; 14.BF.26.157; 14.BF.26.158; 14.BF.26.196;14.BF.26.223; 14.BF.26.240; 14.BF.26.244; 14.BF.26.243; 14.BF.26.247;14.BF.27.157; 14.BF.27.158; 14.BF.27.196; 14.BF.27.223; 14.BF.27.240;14.BF.27.244; 14.BF.27.243; 14.BF.27.247; 14.BF.29.157; 14.BF.29.158;14.BF.29.196; 14.BF.29.223; 14.BF.29.240; 14.BF.29.244; 14.BF.29.243;14.BF.29.247; 14.BF.54.157; 14.BF.54.158; 14.BF.54.196; 14.BF.54.223;14.BF.54.240; 14.BF.54.244; 14.BF.54.243; 14.BF.54.247; 14.BF.55.157;14.BF.55.158; 14.BF.55.196; 14.BF.55.223; 14.BF.55.240; 14.BF.55.244;14.BF.55.243; 14.BF.55.247; 14.BF.56.157; 14.BF.56.158; 14.BF.56.196;14.BF.56.223; 14.BF.56.240; 14.BF.56.244; 14.BF.56.243; 14.BF.56.247;14.BF.157.157; 14.BF.157.158; 14.BF.157.196; 14.BF.157.223;14.BF.157.240; 14.BF.157.244; 14.BF.157.243; 14.BF.157.247;14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF.196.223;14.BF.196.240; 14.BF.196.244; 14.BF.196.243; 14.BF.196.247;14.BF.223.157; 14.BF.223.158; 14.BF.223.196; 14.BF.223.223;14.BF.223.240; 14.BF.223.244; 14.BF.223.243; 14.BF.223.247;14.BF.240.157; 14.BF.240.158; 14.BF.240.196; 14.BF.240.223;14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247;14.BF.244.157; 14.BF.244.158; 14.BF.244.196; 14.BF.244.223;14.BF.244.240; 14.BF.244.244; 14.BF.244.243; 14.BF.244.247;14.BF.247.157; 14.BF.247.158; 14.BF.247.196; 14.BF.247.223;14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247; Prodrugs of14.CI 14.CI.4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240;14.CI.4.244; 14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158;14.CI.5.196; 14.CI.5.223; 14.CI.5.240; 14.CI.5.244; 14.CI.5.243;14.CI.5.247; 14.CI.7.157; 14.CI.7.158; 14.CI.7.196; 14.CI.7.223;14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247; 14.CI.15.157;14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240; 14.CI.15.244;14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196;14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243; 14.CI.16.247;14.CI.18.157; 14.CI.18.158; 14.CI.18.196; 14.CI.18.223; 14.CI.18.240;14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CI.26.157; 14.CI.26.158;14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243;14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223;14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157;14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244;14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196;14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247;14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240;14.CI.55.244; 14.CI.55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158;14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243;14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196;14.CI.157.223; 14.CI.157.240; 14.CI.157.244; 14.CI.157.243;14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196;14.CI.196.223; 14.CI.196.240; 14.CI.196.244; 14.CI.196.243;14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196;14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243;14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196;14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243;14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196;14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243;14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196;14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243;14.CI.247.247; Prodrugs of 14.CO 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223; 14.CO.5.240;14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157; 14.CO.7.158;14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244; 14.CO.7.243;14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196; 14.CO.15.223;14.CO.15.240; 14.CO.15.244; 14.CO.15.243; 14.CO.15.247; 14.CO.16.157;14.CO.16.158; 14.CO.16.196; 14.CO.16.223; 14.CO.16.240; 14.CO.16.244;14.CO.16.243; 14.CO.16.247; 14.CO.18.157; 14.CO.18.158; 14.CO.18.196;14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243; 14.CO.18.247;14.CO.26.157; 14.CO.26.158; 14.CO.26.196; 14.CO.26.223; 14.CO.26.240;14.CO.26.244; 14.CO.26.243; 14.CO.26.247; 14.CO.27.157; 14.CO.27.158;14.CO.27.196; 14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243;14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.CO.29.196; 14.CO.29.223;14.CO.29.240; 14.CO.29.244; 14.CO.29.243; 14.CO.29.247; 14.CO.54.157;14.CO.54.158; 14.CO.54.196; 14.CO.54.223; 14.CO.54.240; 14.CO.54.244;14.CO.54.243; 14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196;14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243; 14.CO.55.247;14.CO.56.157; 14.CO.56.158; 14.CO.56.196; 14.CO.56.223; 14.CO.56.240;14.CO.56.244; 14.CO.56.243; 14.CO.56.247; 14.CO.157.157; 14.CO.157.158;14.CO.157.196; 14.CO.157.223; 14.CO.157.240; 14.CO.157.244;14.CO.157.243; 14.CO.157.247; 14.CO.196.157; 14.CO.196.158;14.CO.196.196; 14.CO.196.223; 14.CO.196.240; 14.CO.196.244;14.CO.196.243; 14.CO.196.247; 14.CO.223.157; 14.CO.223.158;14.CO.223.196; 14.CO.223.223; 14.CO.223.240; 14.CO.223.244;14.CO.223.243; 14.CO.223.247; 14.CO.240.157; 14.CO.240.158;14.CO.240.196; 14.CO.240.223; 14.CO.240.240; 14.CO.240.244;14.CO.240.243; 14.CO.240.247; 14.CO.244.157; 14.CO.244.158;14.CO.244.196; 14.CO.244.223; 14.CO.244.240; 14.CO.244.244;14.CO.244.243; 14.CO.244.247; 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;

All literature and patent citations herein are hereby expresslyincorporated by reference at the locations of their citation.Specifically cited sections or pages of the above cited works areincorporated by reference with specificity. The invention has beendescribed in detail sufficient to allow one of ordinary skill in the artto make and use the subject matter of the following claims. It isapparent that certain modifications of the methods and compositions ofthe following claims can be made within the scope and spirit of theinvention.

In the claims hereinbelow, the subscript and superscripts of a givenvariable are distinct. For example, R₁ is distinct from R¹.

1. A conjugate comprising an anti-inflammatory compound linked to one ormore phosphonate groups; or a pharmaceutically acceptable salt orsolvate thereof.
 2. The conjugate of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, that is a compound of any one offormulae 500-611 substituted with one or more groups A⁰, wherein: A⁰ isA¹, A² or W³ with the proviso that the conjugate includes at least oneA¹;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O.N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is independently H, R¹, R², W³, aprotecting group, or the formula:

wherein: R^(y) is independently H, W³, R² or a protecting group; R¹ isindependently H or alkyl of 1 to 18 carbon atoms; R² is independently H,R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³groups or taken together at a carbon atom, two R² groups form a ring of3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups; R³is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocycleor heterocycle wherein W⁵ is independently substituted with 0 to 3 R²groups; W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups; M2is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d areindependently 0 or 1; M12cis 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;X⁶⁶ is hydrogen or fluorine; and X⁶⁷ is hydrogen, hydroxy, or acyloxy.3. The conjugate of claim 2, or a pharmaceutically acceptable salt orsolvate thereof, which has the formula:[DRUG]-(A⁰)_(nn) wherein: DRUG is a compound of any one of formulae500-611; and nn is 1, 2, or
 3. 4. The conjugate of claim 2 which has anyone of formulae 1-296 wherein: one A⁰ is A¹; X⁵⁰ is H or F; X⁵¹ is H,hydroxy, or acyloxy; X⁵² is NH₂ or EtC(O)N—Na+; X⁵³ is H, methyl, CF₃,or halo; X⁵⁴ is H, halo, trifluoromethyl, (C₁-C₃)alkyl, cyano, or(C₁-C₃)alkoxy; X⁵⁵ is H, F, Cl, Br, methyl, or trifluoromethyl; X⁵⁶ isH, halo, trifluoromethyl, cyano, methyl; X⁵⁷ is H, F, Cl, CF₃, cyano,methyl, or t-butyl; X⁵⁸ is H or CH₂OH; X⁵⁹ is H or F; X⁶⁰ is H,trifluoromethyl, or cyano; X⁶¹ is methoxy, ethoxy, propoxy,difluoromethoxy, trifluoromethoxy, vinyl, ethyl, methyl, propyl, butyl,cyclopropyl, N-methylamino, or N-formylamino; X⁶² is methyl, chloro, ortrifluoromethyl; X⁶³ is H, methyl, ethyl, cyclopropyl, vinyl, ortrifluoromethyl; X⁶⁴ is H, methyl, ethyl, cyclopropyl, chloro, vinyl,allyl, 3-methyl-1-buten-1-yl; X⁶⁵ is H or F; and Ar is aryl orheteroaryl. 5-27. (canceled)
 28. The conjugate of claim 2 wherein eachA³ is of the formula:

29-30. (canceled)
 31. The conjugate of claim 2 wherein each A³ is of theformula:

wherein Y^(2b) is O or N(R^(x)). 32-34. (canceled)
 35. The conjugate ofclaim 2 wherein each A³ is of the formula:

36-37. (canceled)
 38. The conjugate of claim 2 wherein each A³ is of theformula:

39-41. (canceled)
 42. The conjugate of claim 2 wherein each A³ is of theformula:

wherein Y^(2b) is O or N(R^(x)). 43-45. (canceled)
 46. The conjugate ofclaim 2 wherein each A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups. 47-51. (canceled)
 52. The conjugate of claim 2 wherein each A³is of the formula:

wherein: Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S. 53-62. (canceled)
 63. The conjugate of claim 3 wherein A⁰is of the formula:

wherein each R is independently alkyl.
 64. The conjugate of claim 1which has the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: DRUGis an anti-inflammatory compound; Y¹ is independently O, S, N(R^(x)),N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² isindependently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)),N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; R^(x) isindependently H, R², W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group; R² isindependently H, R³ or R⁴ wherein each R⁴ is independently substitutedwith 0 to 3 R³ groups; R³ is R^(3a), R^(3b), R^(3c) or R^(3d), providedthat when R³ is bound to a heteroatom, then R³ is R^(3c) or R^(3d);R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂; R^(3b) is Y¹; R^(3c) is R^(x),—N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)),—S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))),—SC(Y¹)R^(x), —SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))),—N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵; W⁵ is carbocycle orheterocycle wherein W⁵ is independently substituted with 0 to 3 R²groups; M2 is 1, 2, or 3; M1a, M1c, and M1d are independently 0 or 1;M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; nn is 1, 2, or 3;and L is a direct bond or a linking group. 65-89. (canceled)
 90. Theconjugate as described in claim 1, which is isolated and purified.91-118. (canceled)
 119. A compound of formula MBF.
 120. The compound ofclaim 119 which is selected from Table
 100. 121. A pharmaceuticalcomposition comprising a pharmaceutical excipient and a conjugate asdescribed claim
 1. 122. A unit dosage form comprising a conjugate asdescribed in claim 1; and a pharmaceutically acceptable excipient. 123.A method for inhibiting inflammatory activity in vitro or in vivocomprising contacting a sample in need of such treatment with aconjugate as described in claim
 1. 124. (canceled)
 125. A method oftreating inflammation in a mammal, comprising administering a conjugateas described in claim 1 to the mammal. 126-127. (canceled)